WO2023215498A2

WO2023215498A2 - Compositions and methods for cd28 antagonism

Info

Publication number: WO2023215498A2
Application number: PCT/US2023/021031
Authority: WO
Inventors: Ying Fu
Original assignee: Modernatx, Inc.
Priority date: 2022-05-05
Filing date: 2023-05-04
Publication date: 2023-11-09
Also published as: WO2023215498A3

Abstract

Described herein are antagonistic CD28 antibodies and antigen-binding fragments thereof, as well as nucleic acids encoding the same. The disclosure also features methods of using such antibodies and nucleic acids to suppress autoimmunity, as well as to promote the protection, healing, and preservation of tissues and organs.

Description

COMPOSITIONS AND METHODS FOR CD28 ANTAGONISM Cross-Reference to Related Application This application claims priority to U.S. Provisional Application Serial No. 63/338,524 filed May 5, 2022, the disclosure of which is incorporated herein by reference. Field of the Invention The present disclosure relates generally to a class of CD28 antibodies, as well as nucleic acids encoding the same, methods of producing such antibodies and nucleic acids, and medical applications of such antibodies and nucleic acids for the treatment or prevention of autoimmune diseases. Background In the United States, more than 24 million people suffer from autoimmune diseases. Currently, methods of treating this class of diseases center around inhibiting autoreactive T cell (e.g., autoreactive CD4+ T cells, autoreactive CD8+ T cells) activation and expansion. Cluster of Differentiation 28 (CD28) is a protein expressed on T cells that provides co-stimulatory signals required for autoreactive T cell activation and expansion. However, CD28 has historically been a challenging protein to antagonize. Therefore, there remains a need for a class of antagonistic CD28 antibodies capable of suppressing CD28 activity, as well as methods of using the same to treat or prevent autoimmune diseases. Summary The present disclosure features antagonistic cluster of differentiation 28 (CD28) antibodies and antigen-binding fragments thereof, as well as nucleic acids encoding such antibodies and antigen-binding fragments and uses of the same for treating a variety of diseases, including autoimmune diseases. In a first aspect, the disclosure features a binding protein, comprising a single- domain antibody that specifically binds CD28, the single-domain antibody comprising a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In some embodiments, the single-domain antibody comprises an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the binding protein may comprise a human serum albumin (HSA) protein attached to the single-domain antibody. In some embodiments, the HSA protein comprises an amino acid sequence of SEQ ID NO: 71 or 157. In some embodiments, the HSA protein is attached to the single-domain antibody via a peptide linker. In some embodiments, the peptide linker comprises an amino acid sequence selected from any one of SEQ ID NOs: 72, 73, and 74. In some embodiments, the binding protein comprises an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 81. In some embodiments the binding protein comprises a leader sequence of SEQ ID NO: 75. In another aspect, the disclosure features a single-domain antibody containing the following complementarity-determining regions (CDRs): (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GDTICGNV (SEQ ID NO: 4); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSIFSINA (SEQ ID NO: 5); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAGPPWWRYGGGSSWYERPREYDY (SEQ ID NO: 7). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADRTGQTVQATYWEYDY (SEQ ID NO: 8). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFTLDYYA (SEQ ID NO: 9); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISSSHGST (SEQ ID NO: 10); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence VVFWGPSVDMITGA (SEQ ID NO: 11). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFTLDYYA (SEQ ID NO: 9); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADLWGSSWYSAVPGNDY (SEQ ID NO: 12). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GDTICISA (SEQ ID NO: 13); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence HPLSLASSWYSS (SEQ ID NO: 14). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTYSTYN (SEQ ID NO: 15); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISWTGSNT (SEQ ID NO: 16); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ATELEFYNRRWPPTLDY (SEQ ID NO: 17). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTFGNYV (SEQ ID NO: 18); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IRWSDGTT (SEQ ID NO: 19); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADVHGELFPQVQSHYDY (SEQ ID NO: 20). In another aspect, the disclosure features a single-domain antibody containing the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTFSAYC (SEQ ID NO: 21); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IMWSDGST (SEQ ID NO: 22); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAGVCDSSRLLTRKYEYGY (SEQ ID NO: 23). In another aspect, the disclosure features an antibody, or antigen-binding fragment thereof, containing the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ESVYSDNR (SEQ ID NO: 24); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence LAS (SEQ ID NO: 25); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AGFKIRGTDGHG (SEQ ID NO: 26); (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFSFHFTYW (SEQ ID NO: 27); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IHAGSTGTT (SEQ ID NO: 28); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARLDDIDDYFNL (SEQ ID NO: 29). In another aspect, the disclosure features an antibody, or antigen-binding fragment thereof, containing the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QSIYSD (SEQ ID NO: 30); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAA (SEQ ID NO: 31); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QSFHGYSGTYG (SEQ ID NO: 32); (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GLSFNVYW (SEQ ID NO: 33); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IGPSGDGKT (SEQ ID NO: 34); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARDYTNAFDL (SEQ ID NO: 35). In another aspect, the disclosure features an antibody, or antigen-binding fragment thereof, containing the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QNIYSD (SEQ ID NO: 36); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAA (SEQ ID NO: 31); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QGFHGSSGSHG (SEQ ID NO: (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFSDRYW (SEQ ID NO: 38); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISAGSNAKT (SEQ ID NO: 39); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARDYANYFDL (SEQ ID NO: 40). In some embodiments of any of the above aspects of the disclosure, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody contains a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody contains a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody contains a light chain variable domain having the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody contains a light chain variable domain having the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody contains a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody contains a light chain variable domain having the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody is bound to a half-life extending moiety, such as a human serum albumin (HSA) or a murine serum albumin (MSA) peptide. In some embodiments, the antibody is bound to an HSA peptide. In some embodiments, the HSA or MSA peptide has an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of any one of SEQ ID NOs: 70-71, or 157. In some embodiments, the HSA or MSA peptide has an amino acid sequence that is at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of an one of SEQ ID NOs: 70-71, or 157. In some embodiments, the HSA or MSA peptide has an amino acid sequence that is at least 95% identical (e.g., 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 70-71, or 157. In some embodiments, the HSA peptide has the amino acid sequence of SEQ ID NO: 71 or 157. In some embodiments, the MSA peptide has the amino acid sequence of SEQ ID NO: 70. In some embodiments, the antibody is covalently bound to the HSA or MSA peptide, such as by way of a peptidic linker comprising one or more glycine and/or serine residues. In some embodiments, the peptidic linker is represented by the formula (G_xS)_y, wherein each x is, independently, an integer of from 1 to 10 and y is an integer of from 1 to 5. In some embodiments, each x is, independently, an integer of from 1 to 5. In some embodiments, each x is 4. In some embodiments, the peptidic linker is GGGGS (SEQ ID NO: 72), GGGGSGGGGS (SEQ ID NO: 73), or GGGGSGGGGSGGGGS (SEQ ID NO: 74). In some embodiments, the C-terminus of the antibody is bound to the N-terminus of the HSA or MSA peptide. In some embodiments, the N-terminus of the antibody is bound to the C-terminus of the HSA or MSA peptide. In some embodiments, the antibody may comprise an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the antibody may be bound to a signal peptide when it is expressed, and the signal peptide may be cleaved off of the mature antibody during post-translational processing. In some embodiments, the signal peptide has an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of METPAQLLFLLLLWLPDTTG (SEQ ID NO: 75). In some embodiments, the amino acid sequence of the signal peptide is at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the amino acid sequence of the signal peptide is at least 95% identical (e.g., 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the signal peptide has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the N-terminus of the antibody is bound to the C-terminus of the signal peptide. In some embodiments, the C-terminus of the antibody is bound to the N-terminus of the signal peptide. In some embodiments, the antibody specifically binds CD28. In some embodiments, the antibody inhibits CD28 signaling. In some embodiments, the antibody binds CD28 with a K_D of no greater than 100 nM (e.g., with a K_D of from 1 nM to 100 nM, such as with a K_D of 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 26 nM, 27 nM, 28 nM, 29 nM, 30 nM, 31 nM, 32 nM, 33 nM, 34 nM, 35 nM, 36 nM, 37 nM, 38 nM, 39 nM, 40 nM, 41 nM, 42 nM, 43 nM, 44 nM, 45 nM, 46 nM, 47 nM, 48 nM, 49 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, 80 nM, 81 nM, 82 nM, 83 nM, 84 nM, 85 nM, 86 nM, 87 nM, 88 nM, 89 nM, 90 nM, 91 nM, 92 nM, 93 nM, 94 nM, 95 nM, 96 nM, 97 nM, 98 nM, 99 nM, or 100 nM). In some embodiments, the antibody binds CD28 with a K_D of 1 nM to 50 nM (e.g., 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 26 nM, 27 nM, 28 nM, 29 nM, 30 nM, 31 nM, 32 nM, 33 nM, 34 nM, 35 nM, 36 nM, 37 nM, 38 nM, 39 nM, 40 nM, 41 nM, 42 nM, 43 nM, 44 nM, 45 nM, 46 nM, 47 nM, 48 nM, 49 nM, or 50 nM). In some embodiments, the antibody binds CD28 with a k_on of greater than 10⁴ M- ¹s^-1, such as from 10³ M^-1s^-1 to 10⁵ M^-1s^-1 (e.g., 1.0 x 10³ M^-1s^-1, 1.5 x 10³ M^-1s^-1, 2.0 x 10³ M^-1s^-1, 2.5 x 10³ M^-1s^-1, 3.0 x 10³ M^-1s^-1, 3.5 x 10³ M^-1s^-1, 4.0 x 10³ M^-1s^-1, 4.5 x 10³ M^-1s^-1, 5.0 x 10³ M^-1s^-1, 5.5 x 10³ M^-1s^-1, 6.0 x 10³ M^-1s^-1, 6.5 x 10³ M^-1s^-1, 7.0 x 10³ M^-1s^-1, 7.5 x 10³ M^-1s^-1, 8.0 x 10³ M^-1s^-1, 8.5 x 10³ M^-1s^-1, 9.0 x 10³ M^-1s^-1, 9.5 x 10³ M^-1s^-1, 1.0 x 10⁴ M^-1s^-1, 1.5 x 10⁴ M^-1s^-1, 2.0 x 10⁴ M^-1s^-1, 2.5 x 10⁴ M^-1s^-1, 3.0 x 10⁴ M^-1s^-1, 3.5 x 10⁴ M^-1s^-1, 4.0 x 10⁴ M^-1s^-1, 4.5 x 10⁴ M^-1s^-1, 5.0 x 10⁴ M^-1s^-1, 5.5 x 10⁴ M^-1s^-1, 6.0 x 10⁴ M^-1s- ¹, 6.5 x 10⁴ M^-1s^-1, 7.0 x 10⁴ M^-1s^-1, 7.5 x 10⁴ M^-1s^-1, 8.0 x 10⁴ M^-1s^-1, 8.5 x 10⁴ M^-1s^-1, 9.0 x 10⁴ M^-1s^-1, 9.5 x 10⁴ M^-1s^-1, or 1.0 x 10⁵ M^-1s^-1). In some embodiments, the antibody binds CD28 with a k_off of less than 10^-3 s^-1, such as from 10^-5 s^-1 to 10^-3 s^-1 (e.g., 1.0 x 10- ³ s^-1, 9.5 x 10^-4 s^-1, 9.0 x 10^-4 s^-1, 8.5 x 10^-4 s^-1, 8.0 x 10 ^-4 s^-1, 7.5 x 10^-4 s^-1, 7.0 x 10^-4 s^-1, 6.5 x 10^-4 s^-1, 6.0 x 10^-4 s^-1, 5.5 x 10^-4 s^-1, 5.0 x 10^-4 s^-1, 4.5 x 10^-4 s^-1, 4.0 x 10^-4 s^-1, 3.5 x 10^-4 s^-1, 3.0 x 10^-4 s^-1, 2.5 x 10^-4 s^-1, 2.0 x 10^-4 s^-1, 1.5 x 10^-4 s^-1, 1.0 x 10^-4 s^-1, 9.5 x 10^-5 s- ¹, 9.0 x 10^-5 s^-1, 8.5 x 10^-5 s^-1, 8.0 x 10^-5 s^-1, 7.5 x 10^-5 s^-1, 7.0 x 10^-5 s^-1, 6.5 x 10^-5 s^-1, 6.0 x 10^-5 s^-1, 5.5 x 10^-5 s^-1, 5.0 x 10^-5 s^-1, 4.5 x 10^-5 s^-1, 4.0 x 10^-5 s^-1, 3.5 x 10^-5 s^-1, 3.0 x 10^-5 s^-1, 2.5 x 10^-5 s^-1, 2.0 x 10^-5 s^-1, 1.5 x 10^-5 s^-1, or 1.0 x 10^-5 s^-1). In some embodiments, the antibody reduces expression of one or more proteins selected from CTLA-4, CD80, CD86, CD95, YMNM, PI3K, PIP3, AKT, IL2, mTOR, and BCL-XL in a CD28-expressing T cell. In some embodiments, the antibody inhibits GrB activation in a CD28-expressing T cell. In some embodiments, the antibody inhibits PD- 1 activation in a CD28-expressing T cell. In some embodiments, the antibody reduces proliferation and/or activity of CD4+ T cells in a subject, optionally wherein the CD4+ T cells are autoreactive T cells. In some embodiments, the antibody reduces proliferation and/or activity of CD8+ T cells in a subject, optionally wherein the CD8+ T cells are autoreactive T cells. In some embodiments, the antibody is a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen- binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody- like protein scaffold, a domain antibody, a Fv fragment, a Fab fragment, a F(ab’)₂ molecule, or a tandem scFv (taFv). In another aspect, the disclosure features a nucleic acid encoding the antibody of any one of the above aspects or embodiments. In some embodiments, the nucleic acid is an mRNA. In some embodiments, the nucleic acid contains, in the 5’-to-3’ direction: (a) a 5’ cap structure; (b) a 5’ untranslated region (UTR); (c) an open reading frame encoding the antibody, wherein the open reading frame consists of nucleosides selected from the group consisting of (i) uridine or a modified uridine, (ii) cytidine or a modified cytidine, (iii) adenosine or a modified adenosine, and (iv) guanosine or a modified guanosine; (d) a 3’ UTR; and (e) a 3’ tailing sequence of linked nucleosides. In some embodiments, the 5’ UTR comprises a nucleic acid sequence of SEQ ID NO: 78. In some embodiments, the 3’ UTR comprises a nucleic acid sequence of SEQ ID NO: 79. In some embodiments, the ORF comprises a nucleic acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the nucleic acid sequence of SEQ ID NO: 77. In some embodiments, the open reading frame of nucleosides selected from the group consisting of (i) a modified uridine, (ii) cytidine, (iii) adenosine, and (iv) guanosine. In some embodiments, the modified uridine is 1-methylpseudouridine, pseudouridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza- uridine, 2-thio-uridine, 4-thio-uridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5- hydroxy-uridine, 5-aminoallyl-uridine, 5-halo-uridine, 3-methyl-uridine, 5-methoxy- uridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5-carboxymethyl- uridine, 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-uridine, 5- carboxyhydroxymethyl-uridine methyl ester, 5-methoxycarbonylmethyl-uridine, 5- methoxycarbonylmethyl-2-thio-uridine, 5-aminomethyl-2-thio-uridine, 5- methylaminomethyl-uridine, 5-methylaminomethyl-2-thio-uridine, 5-methylaminomethyl- 2-seleno-uridine, 5-carbamoylmethyl-uridine, 5-carboxymethylaminomethyl-uridine, 5- carboxymethylaminomethyl-2-thio-uridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine, 5-methyl-2-thio-uridine, 1- methyl-4-thio-pseudouridine, 4-thio-1-methyl-pseudouridine, 3-methylpseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza- pseudouridine, dihydrouridine, dihydropseudouridine, 5,6-dihydrouridine, 5-methyl- dihydrouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2- methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1- methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine, 5-(isopentenylaminomethyl)uridine, 5- (isopentenylaminomethyl)-2-thio-uridine, α-thio-uridine, 2′-O-methyl-uridine, 5,2′-O- dimethyl-uridine, 2′-O-methyl-pseudouridine, 2-thio-2′-O-methyl-uridine, 5- methoxycarbonylmethyl-2′-O-methyl-uridine, 5-carbamoylmethyl-2′-O-methyl-uridine, 5- carboxymethylaminomethyl-2′-O-methyl-uridine, 3,2′-O-dimethyl-uridine, 5- (isopentenylaminomethyl)-2′-O-methyl-uridine, 1-thio-uridine, deoxythymidine, 2’-F-ara- uridine, 2’-F-uridine, 2’-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, or 5-[3-(1-E- propenylamino)uridine. In preferred embodiments, the modified uridine is 1- methylpseudouridine. In some embodiments, the modified cytidine is 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetyl-cytidine, 5-formyl-cytidine, N4-methyl- cytidine, 5-methyl-cytidine, 5-halo-cytidine, 5-hydroxymethyl-cytidine, 1-methyl- pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5- methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1- methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5- aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2- methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4- methoxy-1-methyl-pseudoisocytidine, lysidine, α-thio-cytidine, 2′-O-methyl-cytidine, 5,2′- O-dimethyl-cytidine, N4-acetyl-2′-O-methyl-cytidine, N4,2′-O-dimethyl-cytidine, 5-formyl- 2′-O-methyl-cytidine, N4,N4,2′-O-trimethyl-cytidine, 1-thio-cytidine, 2’-F-ara-cytidine, 2’- F-cytidine, or 2’-OH-ara-cytidine. In some embodiments, the modified adenosine is 2-amino-purine, 2, 6- diaminopurine, 2-amino-6-halo-purine, 6-halo-purine, 2-amino-6-methyl-purine, 8-azido- adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7- deaza-8-aza-2-amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6- diaminopurine, 1-methyl-adenosine, 2-methyl-adenine, N6-methyl-adenosine, 2- methylthio-N6-methyl-adenosine, N6-isopentenyl-adenosine, 2-methylthio-N6- isopentenyl-adenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis- hydroxyisopentenyl)adenosine, N6-glycinylcarbamoyl-adenosine, N6- threonylcarbamoyl-adenosine, N6-methyl-N6-threonylcarbamoyl-adenosine, 2- methylthio-N6-threonylcarbamoyl-adenosine, N6,N6-dimethyl-adenosine, N6- hydroxynorvalylcarbamoyl-adenosine, 2-methylthio-N6-hydroxynorvalylcarbamoyl- adenosine, N6-acetyl-adenosine, 7-methyl-adenine, 2-methylthio-adenine, 2-methoxy- adenine, α-thio-adenosine, 2′-O-methyl-adenosine, N6,2′-O-dimethyl-adenosine, N6,N6,2′-O-trimethyl-adenosine, 1,2′-O-dimethyl-adenosine, 2′-O-ribosyladenosine, 2- amino-N6-methyl-purine, 1-thio-adenosine, 8-azido-adenosine, 2’-F-ara-adenosine, 2’- F-adenosine, 2’-OH-ara-adenosine, or N6-(19-amino-pentaoxanonadecyl)-adenosine. In some embodiments, the modified guanosine is inosine, 1-methyl-inosine, wyosine, methylwyosine, 4-demethyl-wyosine, isowyosine, wybutosine, peroxywybutosine, hydroxywybutosine, 7-deaza-guanosine, queuosine, epoxyqueuosine, galactosyl-queuosine, mannosyl-queuosine, 7-cyano-7-deaza- guanosine, 7-aminomethyl-7-deaza-guanosine, archaeosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl- guanosine, 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6-methoxy-guanosine, 1- methyl-guanosine, N2-methyl-guanosine, N2,N2-dimethyl-guanosine, N2,7-dimethyl- guanosine, N2, N2,7-dimethyl-guanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio- guanosine, α-thio-guanosine, 2′-O-methyl-guanosine, N2-methyl-2′-O-methyl- guanosine, N2,N2-dimethyl-2′-O-methyl-guanosine, 1-methyl-2′-O-methyl-guanosine, N2,7-dimethyl-2′-O-methyl-guanosine, 2′-O-methyl-inosine, 1,2′-O-dimethyl-inosine, 2′- O-ribosylguanosine, 1-thio-guanosine, O6-methyl-guanosine, 2’-F-ara-guanosine, or 2’- F-guanosine. In some embodiments, the 3’ tailing sequence of linked nucleosides is a poly- adenylate (polyA) tail or a polyA-G quartet. In some embodiments, the 3’ tailing sequence of linked nucleosides is a polyA tail. In some embodiments, the polyA tail contains from 100 to 200 contiguous adenosine residues (e.g., about 160 contiguous adenosine residues). In some embodiments, the poly(A) tail comprises or consists of 100 adenine residues. In some embodiments, the 5’ cap structure is Cap0, Cap1, ARCA, inosine, 1- methyl-guanosine, 2′fluoroguanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino- guanosine, LNA-guanosine, or 2-azidoguanosine. In another aspect, the disclosure features a pharmaceutical composition containing the antibody or nucleic acid of any of the above aspects or embodiments of the disclosure. In some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers, diluents, and/or excipients. In some embodiments, the pharmaceutical composition contains a plurality of lipid nanoparticles encapsulating the antibody or nucleic acid. In some embodiments, the pharmaceutical composition contains a plurality of lipid nanoparticles encapsulating the nucleic acid. In some embodiments, the lipid nanoparticles comprise a compound of Formula (I):

(I) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched; wherein R’^branched is:

wherein

denotes a point of attachment; wherein R^aα, R^aβ, R^aγ, and R^aδ are each independently selected from the group consisting of H, C_2-12 alkyl, and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II):

(II) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: ^cyclic

and R’ is: ; and

R’^b is: or

wherein

denotes a point of attachment; R^aγ and R^aδ are each independently selected from the group consisting of H, C_1- ₁₂ alkyl, and C_2-12 alkenyl, wherein at least one of R^aγ and R^aδ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R^bγ and R^bδ are each independently selected from the group consisting of H, C_1- ₁₂ alkyl, and C_2-12 alkenyl, wherein at least one of R^bγ and R^bδ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; Y^a is a C_3-6 carbocycle; R*”^a is selected from the group consisting of C_1-15 alkyl and C_2-15 alkenyl; and s is 2 or 3; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II-a):

wherein R’^a is R’^branched or R’^cyclic; wherein

wherein

denotes a point of attachment; R^aγ and R^aδ are each independently selected from the group consisting of H, C_1- ₁₂ alkyl, and C_2-12 alkenyl, wherein at least one of R^aγ and R^aδ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R^bγ and R^bδ are each independently selected from the group consisting of H, C_1- ₁₂ alkyl, and C_2-12 alkenyl, wherein at least one of R^bγ and R^bδ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting

wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II-b):

wherein R’^a is R’^branched or R’^cyclic; wherein

wherein

denotes a point of attachment; R^aγ and R^bγ are each independently selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting

wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II-c):

(II-c) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: ^b

and R’ is:

; wherein

denotes a point of attachment; wherein R^aγ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

wherein denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R’ is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II-e):

(II-e) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: ^b

and R’ is:

wherein

denotes a point of attachment; wherein R^aγ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; R’ is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the lipid nanoparticles comprise a compound of Formula (II-f):

(II-f) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: ^b

and R’ is:

wherein

denotes a point of attachment; R^aγ is a C_1-12 alkyl; R² and R³ are each independently a C_1-14 alkyl; R⁴ is -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; R’ is a C_1-12 alkyl; m is selected from 4, 5, and 6; and l is selected from 4, 5, and 6. In certain embodiments of the foregoing lipid nanoparticle, the compound is

or its N-oxide, or a salt or isomer thereof. In certain embodiments of the foregoing lipid nanoparticle, the compound is

or its N-oxide, or a salt or isomer thereof. In certain embodiments of the foregoing lipid nanoparticle, the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG-lipid. In certain embodiments, the PEG-lipid is Compound I. In certain embodiments, the PEG-lipid is Compound II. For example, in some embodiments, the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG-lipid, optionally wherein the PEG-lipid is Compound I. In certain embodiments, the lipid nanoparticle comprises: (i) 40-50 mol% of the compound of Formula (I), 30-45 mol% of the structural lipid, 5-15 mol% of the phospholipid, and 1-5 mol% of the PEG-lipid; or (ii) 45-50 mol% of the compound of Formula (I), 35-45 mol% of the structural lipid, 8-12 mol% of the phospholipid, and 1.5 to 3.5 mol% of the PEG-lipid. In certain embodiments, the lipid nanoparticle comprises (a) (i) Compound II, (ii) Cholesterol, and (iii) PEG-DMG or Compound I; (b) (i) Compound VI, (ii) Cholesterol, and (iii) PEG-DMG or Compound I; (c) (i) Compound II, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) PEG-DMG or Compound I; (d) (i) Compound VI, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) PEG-DMG or Compound I; (e) (i) Compound II, (ii) Cholesterol, and (iii) Compound I; (f) (i) Compound II, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) Compound I; (g) (i) Compound B, (ii) Cholesterol, and (iii) PEG- DMG or Compound I; (h) (i) Compound B, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) PEG-DMG or Compound I; (i) (i) Compound B, (ii) Cholesterol, and (iii) Compound I; or (j) (i) Compound B, (ii) DSPC or DOPE, (iii) Cholesterol, and (iv) Compound I. In certain embodiments, the lipid nanoparticle comprises Compound II and Compound I. In certain embodiments, the lipid nanoparticle comprises Compound B and Compound I. In certain embodiments, the lipid nanoparticle comprises Compound II, DSPC, Cholesterol, and Compound I. In some embodiments, the plurality of lipid nanoparticles has a mean particle size of from 80 nm to 160 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 60 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 70 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 80 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 90 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 100 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 110 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 120 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 130 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 140 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 150 nm. In some embodiments, lipid nanoparticles of the disclosure have a mean particle size of about 160 nm. In some embodiments, the plurality of lipid nanoparticles has a polydispersity index (PDI) of from 0.02 to 0.2 (e.g., a PDI of about 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2). In some embodiments, the plurality of lipid nanoparticles has a lipid:nucleic acid ratio of from 10 to 20 (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, the lipid nanoparticles contain a neutral lipid, a cationic lipid, a polyethyleneglycol (PEG) lipid, and/or a sterol. In some embodiments, the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine. In some embodiments, the cationic lipid is selected from:

and

, or N-oxides, salts, or isomers thereof. In some embodiments, the PEG lipid is PEG 2000 dimyristoyl glycerol. In some embodiments, the sterol is cholesterol, adosterol, agosterol A, atheronals, avenasterol, azacosterol, blazein, cerevisterol, colestolone, cycloartenol, daucosterol, 7- dehydrocholesterol, 5-dehydroepisterol, 7-dehydrositosterol, 20α,22R- dihydroxycholesterol, dinosterol, epibrassicasterol, episterol, ergosterol, ergosterol, fecosterol, fucosterol, fungisterol, ganoderenic acid, ganoderic acid, ganoderiol, ganodermadiol, 7α-hydroxycholesterol, 22R-hydroxycholesterol, 27-hydroxycholesterol, inotodiol, lanosterol, lathosterol, lichesterol, lucidadiol, lumisterol, oxycholesterol, oxysterol, parkeol, saringosterol, spinasterol, sterol ester, trametenolic acid, zhankuic acid, or zymosterol. In preferred embodiments, the sterol is cholesterol. In another aspect, the disclosure features a host cell containing the antibody or nucleic acid of any of the above aspects or embodiments. In some embodiments, the host cell is a prokaryotic cell. In some embodiments, the host cell is a eukaryotic cell (e.g., a mammalian cell, such as a CHO cell or HEK cell). In another aspect, the disclosure features a method of making the antibody of any of the above aspects or embodiments, the method including expressing the nucleic acid in the host cell of any one of the above aspects or embodiments. In another aspect, the disclosure features a method of making the antibody of any of the above aspects or embodiments, the method including performing an in vitro transcription reaction using the nucleic acid. In another aspect, the disclosure features a method of reducing proliferation and/or activity of a population of T cells (e.g., CD4+ or CD8+ T cells) in a subject, the method including administering to the subject the antibody, nucleic acid, or pharmaceutical composition of any one of the above aspects or embodiments. In some embodiments, the subject has been diagnosed as having an autoimmune disease. In some embodiments, the T cells are autoreactive T cells. In another aspect, the disclosure features a method of treating an autoimmune disease in a subject in need thereof, the method including administering to the subject the antibody, nucleic acid, or pharmaceutical composition of any of the above aspects or embodiments. In another aspects, the disclosure features a method of treating graft-versus-host disease (GVHD) in a subject in need thereof, the method including administering to the subject the antibody, nucleic acid, or pharmaceutical composition of any of the above aspects or embodiments. In some embodiments, the GVHD arises from a bone marrow transplant or one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T cells, B cells, natural killer cells, and dendritic cells. In some embodiments, the subject is a mammalian subject (e.g., a human). In another aspect, the disclosure features a kit containing the antibody, nucleic acid, or pharmaceutical composition of any of the above aspects or embodiments. In some embodiments, the kit further contains a package insert instructing a user of the kit to administer the antibody, nucleic acid, or pharmaceutical composition to a subject (e.g., a subject diagnosed as having a disease described herein, such as an autoimmune disease of the preceding embodiments of the disclosure. Brief Description of the Figures FIGS. 1A-C are a set of graphs showing that 8-week-old female NOD-scid IL2Ry^null (NSG) mice intravenously treated with 0.25 mg/kg lipid nanoparticles containing aCD28-MSA mRNA maintained normal body weights and had reduced serum alanine aminotransferase (ALT) levels compared to control treatments in a murine model of xeno Graft Versus Host Disease (xGVHD). FIG.1A shows a timeline of the treatments. Treatment began on day 8. FIGS.2A-C are a set of graphs showing that intravenous treatment of 8-week-old female xGVHD mice with 0.25 mg/kg lipid nanoparticles containing aCD28-MSA mRNA, compared to control treatments, resulted in fewer activated hCD45+ T cells in the blood, spleen, and liver. FIGS.3A-F are a set of graphs showing that, in a murine model of xGVHD, 8- week-old female mice treated intravenously twice weekly with 0.25 mg/kg lipid nanoparticles containing aCD28-MSA mRNA exhibited fewer hCD8+ T cells with expression of activation markers CD28 (FIGS.3A-3C) and PD1 (FIGS.3D-3F) compared to control treatments. FIGS.4A-C are a set of graphs showing that twice weekly administration of 0.25 mg/kg lipid nanoparticles containing aCD28-MSA mRNA in hCD28ki mice, compared to control treatments, resulted in receptor occupancy of between 80-90% in mCD4+ and mCD8+ T cells (FIG.4B), as measured 24 hours after the 3^rd treatment, along with a decrease in serum levels of anti-keyhole limpet hemocyanin (KLH) (FIG.4C) in a murine model of T-cell dependent antibody response (TDAR). FIG.4A contains a timeline of the treatments. 12.5 mg/kg KLH was subcutaneously administered on day 1 and day 15 to induce TDAR. FIGS.5A-D are a set of graphs showing the results of once weekely 60 minute intravenous fusion of PBS or 0.2, 0.5 and 1.5 mg/kg LNP-1B containing I-A-HSA in four groups of monkeys (n=6 females) for 3 weeks (days 0, 7, and 14). All monkeys were immunized with KLH 24 hours after the day 0 dosing of the I-A-HSA. I-A-HSA-related changes included dose-dependent increases in the RO% values on CD4+ T helper (FIG.5A) and CD8+ T cytotoxic lymphocytes (FIG.5B) and decreases in anti-KLH IgM (FIG.5C) and IgG (FIG.5D) in plasma. Detailed Description The compositions and methods of the disclosure feature antagonistic cluster of differentiation 28 (CD28) antibodies and nucleic acids encoding the same, as well as methods of using such antibodies and nucleic acids encoding such antibodies for the treatment of a variety of autoimmune diseases. In some embodiments, the antibodies are full-length antibodies that include a pair of heavy chains and a pair of light chains, each containing a variable domain and a constant domain. In some embodiments, the antibodies are single-domain antibodies or single chain Fv (scFv) molecules, among other antigen-binding fragments described herein. In a preferred embodiment, the antibodies are single domain antibodies, e.g., VHH antibodies. The compositions and methods of the disclosure exhibit a series of beneficial biochemical properties that are particularly advantageous for suppressing autoimmunity. For example, the antibodies and antibody fragments herein are capable of robust antagonism of the CD28 receptor. The antibodies and antigen-binding fragments may inhibit the activation and/or proliferation of autoreactive CD4+ and/or CD8+ T cells. Furthermore, antibodies and antigen-binding fragments herein may suppress cytokine production (e.g., interleukin 2 (IL-2), interleukin 10 (IL-10), and interferon gamma (IFNy)). Antibodies and antigen-binding fragments described herein may also reduce expression of autoreactive T cell effector molecules, including granzyme B (GrB) and perforin. Through these activities, the antibodies and antigen-binding fragments may reduce and/or abrogate inappropriate immune reactions. Exemplary antagonistic CD28 antibodies and antigen-binding fragments of the disclosure, along with the amino acid sequences of their corresponding complementarity-determining regions (CDRs), are summarized in Table 1, below. Table 1. Exemplary antagonistic CD28 antibodies of the disclosure

Structural Characteristics of Exemplary Antagonistic CD28 Antibodies Among the molecular features of antagonistic CD28 antibodies, it will be appreciated by one of skill in the art that the CDRs are those regions that predominantly dictate the CD28-binding properties of the molecule. This section provides amino acid sequence information for the CDRs of exemplary antagonistic CD28 antibodies of the disclosure. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of any one of antibodies I-A to I-J, described in Table 1, above. Antibodies I-A through I-J, which are described in further detail in the Working Examples, below, are single-domain antibodies. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibodies I-A through I-J of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a single variable domain on a heavy chain (VHH) having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-A, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNSKNTVYLQMNSLRAEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody I-A, SEQ ID NO: 41) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 41. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-B, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKGLELVSAITSGGS AYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-B, SEQ ID NO: 42) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-C, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKGRELVSAITSGGS AYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-C, SEQ ID NO: 43) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-D, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKGRELVSAITSGGS ATYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-D, SEQ ID NO: 44) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 44. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-E, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKGRELVSAITSGGS ATYEDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-E, SEQ ID NO: 45) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-F, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKGRELVSAITSGGS ATYEDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody I-F, SEQ ID NO: 46) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-G, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVSAITSGGS ATYEDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody I-G, SEQ ID NO: 47) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-H, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-H, SEQ ID NO: 48) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-I, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAADNWGIVRWRAPDYWG QGTLVTVSS (VHH of antibody I-I, SEQ ID NO: 49) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody I-J, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNSKNTVYLQMNSLKPEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody I-J, SEQ ID NO: 50) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 50. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-A, described in Table 1, above. Antibody II-A, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-A of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-A, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody II-A, SEQ ID NO: 51) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 51. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-B, described in Table 1, above. Antibody II-B, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-B of the Working Examples: (a) a CDR-H1 having the amino acid sequence GDTICGNV (SEQ ID NO: 4) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 4; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-B, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGDTICGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody II-B, SEQ ID NO: 52) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 52. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-C, described in Table 1, above. Antibody II-C, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-C of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSIFSINA (SEQ ID NO: 5) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 5; (b) a CDR-H2 having the amino acid sequence ITSGGST (SEQ ID NO: 6) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 6; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-C, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGSIFSINAMGWYRQAPGKQRELVAAITSGGST YYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody II-C, SEQ ID NO: 53) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 53. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-D, described in Table 1, above. Antibody II-D, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-D of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AAGPPWWRYGGGSSWYERPREYDY (SEQ ID NO: 7) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 7. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-D, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAAGPPWWRYGGGSSWYE RPREYDYWGQGTLVTVSS (VHH of antibody II-D, SEQ ID NO: 54) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 54. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-E, described in Table 1, above. Antibody II-E, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-E of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AADRTGQTVQATYWEYDY (SEQ ID NO: 8) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-E, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADRTGQTVQATYWEYDY WGQGTLVTVSS (VHH of antibody II-E, SEQ ID NO: 55) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 55. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-F, described in Table 1, above. Antibody II-F, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-F of the Working Examples: (a) a CDR-H1 having the amino acid sequence GFTLDYYA (SEQ ID NO: 9) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 9; (b) a CDR-H2 having the amino acid sequence ISSSHGST (SEQ ID NO: 10) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 10; and (c) a CDR-H3 having the amino acid sequence VVFWGPSVDMITGA (SEQ ID NO: 11) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 11. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-F, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGDSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVSCISSSHGS TYYADSVKGRFTISRDNAKNTLYFQMNSLKPEDTAVYYYVVFWGPSVDMITGARGQG TLVTVSS (VHH of antibody II-F, SEQ ID NO: 56) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 56. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-G, described in Table 1, above. Antibody II-G, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-G of the Working Examples: (a) a CDR-H1 having the amino acid sequence GFTLDYYA (SEQ ID NO: 9) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 9; (b) a CDR-H2 having the amino acid sequence ITSGGST (SEQ ID NO: 6) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 6; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-G, shown below (CDR sequences shown in bold): EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKQRELVAAITSGGST NYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody II-G, SEQ ID NO: 57) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 57. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-H, described in Table 1, above. Antibody II-H, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-H of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence AADLWGSSWYSAVPGNDY (SEQ ID NO: 12) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-H, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADLWGSSWYSAVPGNDY WGQGTLVTVSS (VHH of antibody II-H, SEQ ID NO: 58) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 58. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-I, described in Table 1, above. Antibody II-I, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-I of the Working Examples: (a) a CDR-H1 having the amino acid sequence GDTICISA (SEQ ID NO: 13) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 13; (b) a CDR-H2 having the amino acid sequence ITSGGST (SEQ ID NO: 6) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 6; and (c) a CDR-H3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-I, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGDTICISAMGWYRQAPGKERELVAAITSGGST NYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADNWGIVRWRAPDYWGQ GTLVTVSS (VHH of antibody II-I, SEQ ID NO: 59) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 59. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody II-J, described in Table 1, above. Antibody II-J, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody II-J of the Working Examples: (a) a CDR-H1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 1; (b) a CDR-H2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 2; and (c) a CDR-H3 having the amino acid sequence HPLSLASSWYSS (SEQ ID NO: 14) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody II-J, shown below (CDR sequences shown in bold): EVQLVESGGGLVQAGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGS ATYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCHPLSLASSWYSSWGQGTL VTVSS (VHH of antibody II-J, SEQ ID NO: 60) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 60. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody III-A, described in Table 1, above. Antibody III-A, which is described in further detail in the Working Examples, below, is a single-domain antibody (VHH). For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody III-A of the Working Examples: (a) a CDR-H1 having the amino acid sequence GRTYSTYN (SEQ ID NO: 15) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 15; (b) a CDR-H2 having the amino acid sequence ISWTGSNT (SEQ ID NO: 16) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 16; and (c) a CDR-H3 having the amino acid sequence ATELEFYNRRWPPTLDY (SEQ ID NO: 17) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 17. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody III-A, shown below (CDR sequences shown in bold): QVQLVESGGGLVQAGGSLRLSCVASGRTYSTYNMGWFRQAPGKEREFVAAISWTGS NTQYASSVKGRFTISRDNAKSSVYLQMNSLKPEDTAVYYCATELEFYNRRWPPTLDY WGQGTQVTVSS (VHH of antibody III-A, SEQ ID NO: 61) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 61. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody III-B, described in Table 1, above. Antibody III-B, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody III-B of the Working Examples: (a) a CDR-H1 having the amino acid sequence GRTFGNYV (SEQ ID NO: 18) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 18; (b) a CDR-H2 having the amino acid sequence IRWSDGTT (SEQ ID NO: 19) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 19; and (c) a CDR-H3 having the amino acid sequence AADVHGELFPQVQSHYDY (SEQ ID NO: 20) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody III-B, shown below (CDR sequences shown in bold): QVQLVESGGGLVQAGDSLRLSCAASGRTFGNYVMGWFRQAPGKEREFVAAIRWSDG TTYYPMSVKGRFTISRDNAKNTMYLQMNTLKSEDTAVYFCAADVHGELFPQVQSHYD YWGQGTQVTVSS (VHH of antibody III-B, SEQ ID NO: 62) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 62. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody III-C, described in Table 1, above. Antibody III-C, which is described in further detail in the Working Examples, below, is a single-domain antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof (e.g., a single-domain antibody) having one or more, or all, of the following CDRs, which are present in antibody III-C of the Working Examples: (a) a CDR-H1 having the amino acid sequence GRTFSAYC (SEQ ID NO: 21) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 21; (b) a CDR-H2 having the amino acid sequence IMWSDGST (SEQ ID NO: 22) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 22; and (c) a CDR-H3 having the amino acid sequence AAGVCDSSRLLTRKYEYGY (SEQ ID NO: 23) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the VHH of antibody III-C, shown below (CDR sequences shown in bold): QVQLVESGGGMVQAGDSLRLSCAAFGRTFSAYCMSWFRQAPGKEREFVAAIMWSD GSTYYENSRKGRFTISRDNAKNTVYLQLNSLKPEDTAVYYCAAGVCDSSRLLTRKYEY GYWGQGTQVTVSS (VHH of antibody III-C, SEQ ID NO: 63) In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody or antigen-binding fragment contains a VHH having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody or antigen-binding fragment contains a VHH having the amino acid sequence of SEQ ID NO: 63. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody IV-A, described in Table 1, above. Antibody IV-A, which is described in further detail in the Working Examples, below, is a full-length monoclonal antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof having one or more, or all, of the following CDRs, which are present in antibody IV-A of the Working Examples: (a) a CDR-L1 having the amino acid sequence ESVYSDNR (SEQ ID NO: 24) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 24; (b) a CDR-L2 having the amino acid sequence LAS (SEQ ID NO: 25) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to LAS; (c) a CDR-L3 having the amino acid sequence AGFKIRGTDGHG (SEQ ID NO: 26) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 26; (d) a CDR-H1 having the amino acid sequence GFSFHFTYW (SEQ ID NO: 27) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 27; (e) a CDR-H2 having the amino acid sequence IHAGSTGTT (SEQ ID NO: 28) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 28; and (f) a CDR-H3 having the amino acid sequence ARLDDIDDYFNL (SEQ ID NO: 29) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 29. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_H of antibody IV-A, shown below (CDR sequences shown in bold): GVQCQEHLEESGVDLVKPEGSLTLTCTASGFSFHFTYWICWVRQAPGKGLEWTACIH AGSTGTTYYATWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCARLDDIDDYFNLWG PGTLVTVSS (V_H of antibody IV-A, SEQ ID NO: 65) In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody or antigen-binding fragment contains aV_H having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody or antigen-binding fragment contains a V_H having the amino acid sequence of SEQ ID NO: 65. In some embodiments, the antibody or antigen-binding fragment contains a light chain variable domain (V_L) having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_L of antibody IV-A, shown below (CDR sequences shown in bold): AIVMTQTPSSVSAAVGGTVTINCQASESVYSDNRLSWFQQKPGQPPKLLIYLASTLAS GVPSRFKGSGSGTLFTLTISDVVCDDAATYYCAGFKIRGTDGHGFGGGTEVVVK ( V_L of antibody IV-A, SEQ ID NO: 64) In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the antibody or antigen-binding fragment contains a V_L having the amino acid sequence of SEQ ID NO: 64. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody IV-B, described in Table 1, above. Antibody IV-B, which is described in further detail in the Working Examples, below, is a full-length monoclonal antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof having one or more, or all, of the following CDRs, which are present in antibody IV-B of the Working Examples: (a) a CDR-L1 having the amino acid sequence QSIYSD (SEQ ID NO: 30) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 30; (b) a CDR-L2 having the amino acid sequence AAA (SEQ ID NO: 31)or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to (SEQ ID NO: 31); (c) a CDR-L3 having the amino acid sequence QSFHGYSGTYG (SEQ ID NO: 32) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 32; (d) a CDR-H1 having the amino acid sequence GLSFNVYW (SEQ ID NO: 33) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 33; (e) a CDR-H2 having the amino acid sequence IGPSGDGKT (SEQ ID NO: 34) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 34; and (f) a CDR-H3 having the amino acid sequence ARDYTNAFDL (SEQ ID NO: 35) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_H of antibody IV-B, shown below (CDR sequences shown in bold): GVQCQSLEESGGDLVKPEGSLTLTCKASGLSFNVYWICWVRQAPGKGLEWIACIGPS GDGKTAYASWAKGRFTISKTSSTTVTLQMTSLTVADTATYFCARDYTNAFDLWGPGT LVTVSS (V_H of antibody IV-B, SEQ ID NO: 67) In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody or antigen-binding fragment contains a V_H having the amino acid sequence of SEQ ID NO: 67. In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_L of antibody IV-B, shown below (CDR sequences shown in bold): DIVMTQTPGSVEAAVGGTVTIKCQASQSIYSDLAWYQQKPGQRPKLLIYAAANLASGV PSRFKGSRSGTEFTLTISDLECADAATYYCQSFHGYSGTYGFGGGTEVVV (V_L of antibody IV-B, SEQ ID NO: 66) In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the antibody or antigen-binding fragment contains a V_L having the amino acid sequence of SEQ ID NO: 66. In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof having one or more, or all, of the CDRs of antibody IV-C, described in Table 1, above. Antibody IV-C, which is described in further detail in the Working Examples, below, is a full-length monoclonal antibody. For example, in some embodiments, the antagonistic CD28 antibody of the disclosure is an antibody or antigen-binding fragment thereof having one or more, or all, of the following CDRs, which are present in antibody IV-C of the Working Examples: (a) a CDR-L1 having the amino acid sequence QNIYSD (SEQ ID NO: 36) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 36; (b) a CDR-L2 having the amino acid sequence AAA (SEQ ID NO: 31) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to (SEQ ID NO: 31); (c) a CDR-L3 having the amino acid sequence QGFHGSSGSHG (SEQ ID NO: 37) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 37; (d) a CDR-H1 having the amino acid sequence GFSDRYW (SEQ ID NO: 38) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 38; (e) a CDR-H2 having the amino acid sequence ISAGSNAKT (SEQ ID NO: 39) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 39; and (f) a CDR-H3 having the amino acid sequence ARDYANYFDL (SEQ ID NO: 40) or an amino acid sequence having up to two amino acid substitutions (e.g., conservative amino acid substitutions) relative to SEQ ID NO: 40. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_H of antibody IV-C, shown below (CDR sequences shown in bold): GVQCQSLEESGGDLVKPEGSLTLTCTASGFSFDRYWICWVRQAPGKGLEWIACISAG SNAKTYHASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDYANYFDLWGPGT LVTVSS (V_H of antibody IV-C, SEQ ID NO: 69) In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody or antigen-binding fragment contains a V_H having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody or antigen-binding fragment contains a V_H having the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 85% identical (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of the V_L of antibody IV-C, shown below (CDR sequences shown in bold): DIVMTQTPASVEAAVGGTVTIKCQASQNIYSDLAWYQQKPGQRPKVLIAAAANLASGV PSRFKGSRSGTEFTLTISDLECADAATYYCQGFHGSSGSHGFGGGTEVVVK (V_L of antibody IV-C, SEQ ID NO: 68) In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody or antigen-binding fragment contains a V_L having an amino acid sequence that is at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the antibody or antigen-binding fragment contains a V_L having the amino acid sequence of SEQ ID NO: 68. Biological Activities of Exemplary Antagonistic CD28 Antibodies Effects on CD4+ and/or CD8+ T cells Exemplary antagonistic CD28 antibodies described herein, such as full-length antibodies, single-domain antibodies, and antigen-binding fragments thereof, may specifically bind CD28 and reduce and/or abrogate CD28 signal transduction, thereby suppressing the activation and proliferation of naïve autoreactive T cells (e.g., autoreactive CD4+ and/or CD8+ T cells). For example, antagonistic CD28 antibodies of the disclosure may antagonize the CD28 receptor, reduce and/or abrogate CD4+ and/or CD8+ T cell activation and proliferation, suppress cytokine production (e.g., IL-2, IL-10, and IFNy), reduce the expression of cytotoxic T cell effector molecules (e.g., GrB), and/or ultimately reduce inappropriate autoimmune activity. Additionally, the antagonistic CD28 antibodies described herein may prevent the activation of naïve autoreactive T cells into autoreactive CD4+ and/or CD8+ T cells. The antibodies of the disclosure may additionally reduce and/or abrogate autoreactive CD4+ and/or CD8+ T cell proliferation, which further suppresses cytokine production and inhibits the expression of autoreactive T cell effector molecules, including granzyme B (GrB) and perforin. Effects on CD28 on signal transduction cascades Exemplary antagonistic CD28 antibodies described herein are capable of interacting with, and inhibiting the activity of, the CD28 receptor. Exemplary antagonistic CD28 antibodies of the disclosure inhibit CD28 co-stimulatory activity, which, in turn, may promote a reduction in the level of one or more mRNA molecules encoding a protein selected from the group including CTLA-4, CD80, CD86, a protein involved in the apoptotic pathway, YMNM, PI3K, PIP3, AKT, a protein involved in the NFkB pathway, IL2, mTOR, and BCL-XL. Antagonistic CD28 antibodies of the disclosure may also promote a reduction in the level of one or more proteins selected from the group including CTLA-4, CD80, CD86, CD95, a protein involved in the apoptotic pathway, YMNM, PI3K, PIP3, AKT, a protein involved in the NDkB pathway, IL2, mTOR, and BCL-XL. Exemplary antagonistic CD28 antibodies described herein may promote the inhibition of several proteins of particular therapeutic importance. Without being limited by mechanism, antibodies of the disclosure may inhibit GrB activation and programmed cell death protein 1 (PD-1) activation. This biological activity is particularly significant, as it can ensure fewer CD8+ T cells acquire cytolytic potential. Exemplary antagonistic CD28 antibodies of the disclosure may prevent the activation, expansion, and engraftment of CD4+ and/or CD8+ T cells. The selective inhibition of CD28+ cells and inhibition of T effector cells are some of the phenotypes that underlie the ability of antagonistic CD28 antibodies to treat autoimmunity, GVHD, inflammation, and other indications described herein. One can monitor CD28 inhibition, for example, by measuring the expression of genes associated with the CD28 signal cascade, such as the expression of genes whose transcription is mediated by NFκB. Multispecific Antibodies In another aspect, the present disclosure provides multispecific antibodies, for example, bispecific antibodies (BsAbs), that may have binding specificities that are directed towards CD28 and any other antigen, e.g., for a cell-surface protein, receptor, receptor subunit, or tissue-specific antigen, or other non-CD28 antigen. Multispecific antibodies typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen (i.e., CD28 and any other antigen). Each antigen-binding domain of a bispecific antibody can comprise a heavy chain variable domain (VH), a light chain variable domain (VL), or a VH and a VL or a single domain antibody (e.g., a VHH). In the context of a bispecific antigen- binding fragment comprising a first and a second antigen-binding domain (e.g., a bispecific antibody), each antigen binding domain comprises at least one CDR that alone, or in combination with one or more additional CDRs and/or framework regions, specifically binds to a particular antigen (i.e., CD28, any other antigen). Affinity of Antibodies of the Disclosure for CD28 Thermodynamic properties of antagonistic CD28 antibodies Antibodies of the disclosure may have an affinity for the CD28 receptor of, for example, from 1 nM to 100 nM (e.g., from 10 nM to 90 nM, from 20 nM to 80 nM, from 30 nM to 70 nM, from 40 nM to 60 nM, or about 50 nM). In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of from 10 nM to 90 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of from 20 nM to 80 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of from 30 nM to 70 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of from 40 nM to 60 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 100 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 95 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 90 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 85 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 80 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 75 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 70 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 65 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 60 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 55 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 50 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 45 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 40 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 35 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 30 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 25 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 20 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 15 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 10 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 5 nM. In some embodiments, antibodies of the disclosure have an affinity for the CD28 receptor of about 1 nM. The specific binding of an antibody described herein to CD28 can be determined by any of a variety of established methods. The affinity can be represented quantitatively by various measurements, including the concentration of antibody needed to achieve half-maximal activation of the CD28 receptor in vitro or in vivo (EC₅₀) and the equilibrium constant (K_D) of the antibody-CD28 complex dissociation. The equilibrium constant,K_D, which describes the interaction of CD28 with an antibody described herein is the chemical equilibrium constant for the dissociation reaction of a CD28-antibody complex into solvent-separated CD28 and antibody molecules that do not interact with one another. Antibodies described herein include those that specifically bind to CD28 with a K_D value of less than 100 nM (e.g., less than 95 nM, 90 nM, 85 nM, 80 nM, 75 nM, 70 nM, 65 nM, 60 nM, 55 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM). In some embodiments, the antibodies described herein specifically bind to CD28 with a K_D value of less than 10 nM (e.g., less than 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM). Antibodies described herein include those that inhibit CD28-mediated IL-2 release with an EC₅₀ of between about 1-700 nM (e.g., between about 5-650 nM, 10- 600 nM, 25-500 nM, 50-400 nM, 100-300 nM, or about 200 nM). Antibodies described herein can also be characterized by a variety of in vitro binding assays. Examples of experiments that can be used to determine the K_D or EC₅₀ of an antagonistic CD28 antibody include, e.g., surface plasmon resonance, isothermal titration calorimetry, fluorescence anisotropy, ELISA-based assays, gene expression assays, and protein expression assays, among others. ELISA represents a particularly useful method for analyzing antibody activity, as such assays typically require minimal concentrations of antibodies. A common signal that is analyzed in a typical ELISA assay is luminescence, which is typically the result of the activity of a peroxidase conjugated to a secondary antibody that specifically binds a primary antibody (e.g., a CD28 antibody described herein). Antibodies described herein may bind CD28 and fragments thereof. Antibodies described herein may additionally bind isolated peptides derived from CD28 that structurally pre-organize various residues in a manner that simulates the conformation of the above fragments in the native protein. In a direct ELISA experiment, this binding can be quantified, e.g., by analyzing the luminescence that occurs upon incubation of an HRP substrate (e.g., 2,2’-azino-di-3- ethylbenzthiazoline sulfonate) with an antigen-antibody complex bound to a HRP- conjugated secondary antibody. Kinetic properties of antagonistic CD28 antibodies In addition to the thermodynamic parameters of a CD28-antibody interaction, it is also possible to quantitatively characterize the kinetic association and dissociation of an antibody described herein with CD28. This can be done, e.g., by monitoring the rate of antibody-antigen complex formation according to established procedures. For example, one can use surface plasmon resonance (SPR) to determine the rate constants for the formation (k_on) and dissociation (k_off) of an antibody-CD28 complex. These data also enable calculation of the equilibrium constant of (K_D) of antibody-CD28 complex dissociation, since the equilibrium constant of this unimolecular dissociation can be expressed as the ratio of the k_off to k_on values. SPR is a technique that is particularly advantageous for determining kinetic and thermodynamic parameters of receptor- antibody interactions since the experiment does not require that one component be modified by attachment of a chemical label. Rather, the receptor is typically immobilized on a solid metallic surface which is treated in pulses with solutions of increasing concentrations of antibody. Antibody-receptor binding induces distortion in the angle of reflection of incident light at the metallic surface, and this change in refractive index over time as antibody is introduced to the system can be fit to established regression models in order to calculate the association and dissociation rate constants of an antibody-receptor interaction. Antibodies described herein may exhibit high k_on and low k_off values upon interaction with CD28, consistent with high-affinity receptor binding. For example, antibodies described herein may exhibit k_on values in the presence of CD28 of greater than 10⁴ M^-1s^-1 (e.g., 1.0 x 10⁴ M^-1s^-1, 1.5 x 10⁴ M^-1s^-1, 2.0 x 10⁴ M^-1s^-1, 2.5 x 10⁴ M^-1s^-1, 3.0 x 10⁴ M^-1s^-1, 3.5 x 10⁴ M^-1s^-1, 4.0 x 10⁴ M^-1s^-1, 4.5 x 10⁴ M^-1s^-1, 5.0 x 10⁴ M^-1s^-1, 5.5 x 10⁴ M^-1s^-1, 6.0 x 10⁴ M^-1s^-1, 6.5 x 10⁴ M^-1s^-1, 7.0 x 10⁴ M^-1s^-1, 7.5 x 10⁴ M^-1s^-1, 8.0 x 10⁴ M- ¹s^-1, 8.5 x 10⁴ M^-1s^-1, 9.0 x 10⁴ M^-1s^-1, 9.5 x 10⁴ M^-1s^-1, 1.0 x 10⁵ M^-1s^-1, 1.5 x 10⁵ M^-1s^-1, 2.0 x 10⁵ M^-1s^-1, 2.5 x 10⁵ M^-1s^-1, 3.0 x 10⁵ M^-1s^-1, 3.5 x 10⁵ M^-1s^-1, 4.0 x 10⁵ M^-1s^-1, 4.5 x 10⁵ M^-1s^-1, 5.0 x 10⁵ M^-1s^-1, 5.5 x 10⁵ M^-1s^-1, 6.0 x 10⁵ M^-1s^-1, 6.5 x 10⁵ M^-1s^-1, 7.0 x 10⁵ M^-1s^-1, 7.5 x 10⁵ M^-1s^-1, 8.0 x 10⁵ M^-1s^-1, 8.5 x 10⁵ M^-1s^-1, 9.0 x 10⁵ M^-1s^-1, 9.5 x 10⁵ M^-1s- ¹, or 1.0 x 10⁶ M^-1s^-1). Antibodies described herein may exhibit low k_off values when bound to CD28. For instance, antibodies described herein may exhibit k_off values of less than 10^-3 s^-1 when complexed to CD28 (e.g., 1.0 x 10^-3 s^-1, 9.5 x 10^-4 s^-1, 9.0 x 10^-4 s^-1, 8.5 x 10^-4 s^-1, 8.0 x 10 ^-4 s^-1, 7.5 x 10^-4 s^-1, 7.0 x 10^-4 s^-1, 6.5 x 10^-4 s^-1, 6.0 x 10^-4 s^-1, 5.5 x 10^-4 s^-1, 5.0 x 10^-4 s^-1, 4.5 x 10^-4 s^-1, 4.0 x 10^-4 s^-1, 3.5 x 10^-4 s^-1, 3.0 x 10^-4 s^-1, 2.5 x 10^-4 s^-1, 2.0 x 10^-4 s^-1, 1.5 x 10^-4 s^-1, 1.0 x 10^-4 s^-1, 9.5 x 10^-5 s^-1, 9.0 x 10^-5 s^-1, 8.5 x 10^-5 s- ¹, 8.0 x 10^-5 s^-1, 7.5 x 10^-5 s^-1, 7.0 x 10^-5 s^-1, 6.5 x 10^-5 s^-1, 6.0 x 10^-5 s^-1, 5.5 x 10^-5 s^-1, 5.0 x 10^-5 s^-1, 4.5 x 10^-5 s^-1, 4.0 x 10^-5 s^-1, 3.5 x 10^-5 s^-1, 3.0 x 10^-5 s^-1, 2.5 x 10^-5 s^-1, 2.0 x 10^-5 s^-1, 1.5 x 10^-5 s^-1, or 1.0 x 10^-5 s^-1). Methods for Humanization of Antibodies Antibodies described herein include fully human, humanized, primatized, and chimeric antibodies that contain one or more, or all, of the CDR sequences shown in Table 1, above. As an example, one strategy that can be used to design humanized antibodies described herein is to align the sequences of the V_H and/or V_L of an antibody of the subject antibody with disclosure with the V_H and/or V_L of a consensus human antibody. Consensus human antibody heavy chain and light chain sequences are known in the art (see e.g., the “VBASE” human germline sequence database; see also Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91 -3242, 1991; Tomlinson et al., J. Mol. Biol.227:776-98, 1992; and Cox et al., Eur. J. Immunol. 24:827-836, 1994; the disclosure of which is incorporated herein by reference). In this way, the variable domain framework residues and CDRs can be identified by sequence alignment (see Kabat, supra). One can then substitute, for example, one or more of the CDRs of the consensus human antibody with the corresponding CDR(s) of an antibody of the disclosure, thereby producing a humanized antibody. Similarly, this strategy can also be used to produce primatized antagonistic CD28 antibodies, as one can substitute, for example, one or more, or all, of the CDRs of a primate antibody consensus sequence with, for example, one or more, or all, of the CDRs of an antibody of the disclosure. Consensus primate antibody sequences known in the art (see e.g., U.S. Patent Nos.5,658,570; 5,681,722; and 5,693,780; the disclosures of each of which are incorporated herein by reference). In some embodiments, it may be desirable to import particular framework residues in addition to CDR sequences from an antagonistic CD28 antibody into the V_H and/or V_L of a human antibody. For instance, US Patent No.6,054,297 identifies several instances when it may be advantageous to retain certain framework residues from a particular antibody heavy chain or light chain variable region in the resulting humanized antibody. In some embodiments, framework residues may engage in non- covalent interactions with the antigen and thus contribute to the affinity of the antibody for the target antigen. In some embodiments, individual framework residues may modulate the conformation of a CDR, and thus indirectly influence the interaction of the antibody with the antigen. Certain framework residues may form the interface between V_H and V_L domains, and may therefore contribute to the global antibody structure. In some cases, framework residues may constitute functional glycosylation sites (e.g., Asn-X-Ser/Thr) which may dictate antibody structure and antigen affinity upon attachment to carbohydrate moieties. In cases such as those described above, it may be beneficial to retain certain framework residues of a CD28 antagonist antibody in, e.g., a humanized or primatized antagonistic antibody or antigen-binding fragment thereof, as various framework residues may promote high epitope affinity and improved biochemical activity of the antibody or antigen-binding fragment thereof. Antibodies described herein also include antibody fragments, Fab domains, F(ab’) molecules, F(ab’)₂ molecules, single-chain variable fragments (scFvs), tandem scFv fragments, diabodies, triabodies, dual variable domain immunoglobulins, multi- specific antibodies, bispecific antibodies, and heterospecific antibodies that contain one or more, or all, of the CDRs of any of the antibodies exemplified in Table 1, above, or a CDR having at least 85% sequence identity thereto (e.g., at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity thereto). These molecules can be expressed recombinantly, e.g., by incorporating polynucleotides encoding these proteins into expression vectors for transfection in a eukaryotic or prokaryotic cell using techniques described herein or known in the art, or synthesized chemically, e.g., by solid phase peptide synthesis methods described herein or known in the art. Antibodies described herein additionally include antibody-like scaffolds that contain, for example, one or more, or all, of the CDRs of any one of the antibodies shown in Table 1, above. Examples of antibody-like scaffolds include proteins that contain a tenth fibronectin type III domain (¹⁰Fn3), which contains BC, DE, and FG structural loops analogous to canonical antibodies. The tertiary structure of the ¹⁰Fn3 domain resembles that of the variable region of the IgG heavy chain, and one of skill in the art can graft, e.g., one or more, or all, of the CDR sequences of an antibody shown in Table 1, above, onto the fibronectin scaffold by replacing residues of the BC, DE, and FG loops of ¹⁰Fn3 with residues of the corresponding CDR sequence. This can be achieved by recombinant expression of a modified ¹⁰Fn3 domain in a prokaryotic or eukaryotic cell (e.g., using the vectors and techniques described herein). Examples of using the ¹⁰Fn3 domain as an antibody-like scaffold for the grafting of CDRs from antibodies onto the BC, DE, and FG structural loops are reported in WO 2000/034784, WO 2009/142773, WO 2012/088006, and U.S. Patent No.8,278,419; the disclosures of each of which are incorporated herein by reference. Nucleic Acids and Expression Systems Antagonistic CD28 antibodies, antigen-binding fragment, or binding proteins described herein can be prepared by any of a variety of established techniques. For instance, an antagonistic CD28 antibodies, antigen binding fragments, and binding proteins described herein can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell. To express an antibody, antigen-binding fragment, or binding protein recombinantly, a host cell can be transfected with one or more recombinant expression vectors carrying DNA fragments encoding the desired antibody chain(s), such that the light and/or heavy chains are expressed in the host cell and, optionally, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered. Standard recombinant DNA methodologies are used to obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Molecular Cloning; A Laboratory Manual, Second Edition (Sambrook, Fritsch and Maniatis (eds), Cold Spring Harbor, N. Y., 1989), Current Protocols in Molecular Biology (Ausubel et al., eds., Greene Publishing Associates, 1989), and in U.S. Patent No.4,816,397; the disclosures of each of which are incorporated herein by reference. Vectors for expression of antagonistic CD28 antibodies Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into the genome of a cell (e.g., a eukaryotic or prokaryotic cell). Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the genome of a target cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents in order to induce gene integration. Examples of viral vectors include a retrovirus, adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., Measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses useful for delivering polynucleotides encoding antibody light and heavy chains or antibody fragments described herein include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus, for example. Examples of retroviruses include: avian leukosis-sarcoma, mammalian C- type, B-type viruses, D-type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields, et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996). Other examples include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses. Other examples of vectors are described, for example, in McVey et al., (U.S. Patent. No.5,801,030); the disclosures of each of which are incorporated herein by reference. Non-viral vectors, such as plasmids, are also well known in the art and include, but are not limited to prokaryotic and eukaryotic vectors (e.g., yeast- and bacteria-based plasmids), as well as plasmids for expression in mammalian cells. Methods of introducing the vectors into a host cell and isolating and purifying the expressed protein are also well known in the art (e.g., Molecular Cloning; A Laboratory Manual, Second Edition (Sambrook, Fritsch and Maniatis (eds), Cold Spring Harbor, N. Y., 1989)). Genome editing techniques In addition to viral vectors, a variety of additional methods have been developed for the incorporation of genes, e.g., those encoding antibody light and heavy chains, single-domain antibodies, single-chain variable fragments (scFvs), tandem scFvs, Fab domains, F(ab’)₂ domains, diabodies, and triabodies, among others, into the genomes of target cells for antibody expression. One such method that can be used for incorporating polynucleotides encoding antagonistic CD28 antibodies into prokaryotic or eukaryotic cells includes the use of transposons. Transposons are polynucleotides that encode transposase enzymes and contain a polynucleotide sequence or gene of interest flanked by excision sites at the 5’ and 3’ positions. Once a transposon has been delivered into a cell, expression of the transposase gene commences and results in active enzymes that cleave the gene of interest from the transposon. This activity is mediated by the site-specific recognition of transposon excision sites by the transposase. In some embodiments, these excision sites may be terminal repeats or inverted terminal repeats. Once excised from the transposon, the gene of interest can be integrated into the genome of a prokaryotic or eukaryotic cell by transposase- catalyzed cleavage of similar excision sites that exist within nuclear genome of the cell. This allows the gene encoding an antagonistic CD28 antibody described herein to be inserted into the cleaved nuclear DNA at the excision sites, and subsequent ligation of the phosphodiester bonds that join the gene of interest to the DNA of the prokaryotic or eukaryotic cell genome completes the incorporation process. In some embodiments, the transposon is a retrotransposon, such that the gene encoding the antibody is first transcribed to an RNA product and then reverse-transcribed to DNA before incorporation in the prokaryotic or eukaryotic cell genome. Exemplary transposon systems include the piggybac transposon (described in detail in WO 2010/085699) and the sleeping beauty transposon (described in detail in US20050112764); the disclosures of each of which are incorporated herein by reference. Another useful method for the integration of nucleic acid molecules encoding antagonistic CD28 antibodies into the genome of a prokaryotic or eukaryotic cell is the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system, which is a system that originally evolved as an adaptive defense mechanism in bacteria and archaea against infection by viruses. The CRISPR/Cas system consists of palindromic repeat sequences within plasmid DNA and an associated Cas9 nuclease. This ensemble of DNA and protein directs site specific DNA cleavage of a target sequence by first incorporating foreign DNA into CRISPR loci. Polynucleotides containing these foreign sequences and the repeat-spacer elements of the CRISPR locus are in turn transcribed in a host cell to create a guide RNA, which can subsequently anneal to a target sequence and localize the Cas9 nuclease to this site. In this manner, highly site- specific cas9-mediated DNA cleavage can be engendered in a foreign polynucleotide because the interaction that brings cas9 within close proximity of the target DNA molecule is governed by RNA:DNA hybridization. As a result, one can theoretically design a CRISPR/Cas system to cleave any target DNA molecule of interest. This technique has been exploited in order to edit eukaryotic genomes (Hwang et al., Nat. Biotech., 31:227-229, 2013) and can be used as an efficient means of site-specifically editing eukaryotic or prokaryotic genomes in order to cleave DNA prior to the incorporation of a polynucleotide encoding an antagonistic CD28 antibodies described herein. The use of CRISPR/Cas to modulate gene expression has been described in US Patent No.8,697,359, the disclosure of which is incorporated herein by reference. Alternative methods for site-specifically cleaving genomic DNA prior to the incorporation of a polynucleotide encoding a CD28 antibody or antibody fragment described herein include the use of zinc finger nucleases and transcription activator-like effector nucleases (TALENs). Unlike the CRISPR/Cas system, these enzymes do not contain a guiding polynucleotide to localize to a specific target sequence. Target specificity is instead controlled by DNA binding domains within these enzymes. Zinc finger nucleases and TALENs for use in genome editing applications are described in Urnov et al. (Nat. Rev. Genet., 11:636-646, 2010); and in Joung et al., (Nat. Rev. Mol. Cell. Bio.14:49-55, 2013); incorporated herein by reference. Additional genome editing techniques that can be used to incorporate polynucleotides encoding antibodies described herein into the genome of a prokaryotic or eukaryotic cell include the use of ARCUS^TM meganucleases that can be rationally designed so as to site-specifically cleave genomic DNA. The use of these enzymes for the incorporation of polynucleotides encoding antagonistic CD28 antibodies described herein into the genome of a prokaryotic or eukaryotic cell is particularly advantageous in view of the structure-activity relationships that have been established for such enzymes. Single- chain meganucleases can thus be modified at certain amino acid positions in order to create nucleases that selectively cleave DNA at desired locations. These single-chain nucleases have been described extensively, e.g., in U.S. Patent Nos.8,021,867 and 8,445,251; the disclosures of each of which are incorporated herein by reference. Polynucleotide sequence elements To express antagonistic CD28 antibodies described herein, polynucleotides encoding partial or full-length light and heavy chains, e.g., polynucleotides that encode a one or more, or all, of the CDR sequences of an antibody or antigen-binding fragment thereof described herein, can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. Polynucleotides encoding the light chain gene and the heavy chain of a CD28 antibody can be inserted into separate vectors, or, optionally, both polynucleotides can be incorporated into the same expression vector using established techniques described herein or known in the art. In addition to polynucleotides encoding the heavy and light chains of an antibody (or a polynucleotide encoding a single-chain antibody, an antibody fragment, such as a scFv molecule, or a construct described herein), the recombinant expression vectors described herein may carry regulatory sequences that control the expression of the antibody chain genes in a host cell. The design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed or the level of expression of protein desired. For instance, suitable regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma. Viral regulatory elements, and sequences thereof, are described in detail, for instance, in U.S. Patent No.5, 168,062, U.S. Patent No.4,510,245, and U.S. Patent No. 4,968,615, the disclosures of each of which are incorporated herein by reference. In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors described herein can carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. A selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Patents Nos. 4,399,216, 4,634,665 and 5,179,017). For example, typically the selectable marker gene confers resistance to cytotoxic drugs, such as G418, puromycin, blasticidin, hygromycin or methotrexate, to a host cell into which the vector has been introduced. Suitable selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in DHFR” host cells with methotrexate selection/amplification) and the neo gene (for G418 selection). In order to express the light and heavy chains of a CD28 antibody or a CD28 antibody fragment, the expression vector(s) containing polynucleotides encoding the heavy and light chains can be transfected into a host cell by standard techniques. Host cells for expression of antagonistic CD28 antibodies It is possible to express the antibodies described herein in either prokaryotic or eukaryotic host cells. In some embodiments, expression of antibodies is performed in eukaryotic cells, e.g., mammalian host cells, for high secretion of a properly folded and immunologically active antibody. Exemplary mammalian host cells for expressing the recombinant antibodies or antigen-binding fragments thereof described herein include Chinese Hamster Ovary (CHO cells) (including DHFR CHO cells, described in Urlaub and Chasin (1980, Proc. Natl. Acad. Sci. USA 77:4216-4220), used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp (1982, Mol. Biol.159:601- 621), NSO myeloma cells, COS cells, 293 cells, and SP2/0 cells. Additional cell types that may be useful for the expression of antibodies and fragments thereof include bacterial cells, such as BL-21(DE3) E. Coli cells, which can be transformed with vectors containing foreign DNA according to established protocols. Additional eukaryotic cells that may be useful for expression of antibodies include yeast cells, such as auxotrophic strains of S. cerevisiae, which can be transformed and selectively grown in incomplete media according to established procedures known in the art. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods. Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. Also included herein are methods in which the above procedure is varied according to established protocols known in the art. For example, in some embodiments, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antagonistic CD28 antibody described herein in order to produce an antigen-binding fragment of the antibody. Once an antagonistic CD28 antibody described herein has been produced by recombinant expression, it can be purified by any method known in the art, such as a method useful for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for CD28 after Protein A or Protein G selection, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the antagonistic CD28 antibodies described herein or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification or to produce therapeutic conjugates. Once isolated, an antagonistic CD28 single-chain antibody can, if desired, be further purified, e.g., by high performance liquid chromatography (see, e.g., Fisher, Laboratory Techniques in Biochemistry and Molecular Biology (Work and Burdon, eds., Elsevier, 1980); incorporated herein by reference), or by gel filtration chromatography, such as on a Superdex^TM 75 column (Pharmacia Biotech AB, Uppsala, Sweden). In some embodiments, the antibody may be bound to a signal peptide when it is expressed, and the signal peptide may be cleaved off of the mature antibody during post-translational processing. In some embodiments, the signal peptide has an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of METPAQLLFLLLLWLPDTTG (SEQ ID NO: 75). In some embodiments, the amino acid sequence of the signal peptide is at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the amino acid sequence of the signal peptide is at least 95% identical (e.g., 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the signal peptide has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the N-terminus of the antibody is bound to the C-terminus of the signal peptide. In some embodiments, the C-terminus of the antibody is bound to the N- terminus of the signal peptide. Half-life Extension Moieties In some embodiments, an antagonistic CD28 antibody of the disclosure is conjugated to a second molecule, e g., to extend the half-life of the antibody in vivo. Antagonistic CD28 antibodies and fragments thereof can be conjugated to other molecules at, e.g., the N-terminus or C-terminus of a light and/or heavy chain of the antibody using any one of a variety of conjugation strategies known in the art. Examples of pairs of reactive functional groups that can be used to covalently tether an antagonistic CD28 antibody or fragment thereof to another molecule include, without limitation, thiol pairs, carboxylic acids and amino groups, ketones and amino groups, aldehydes and amino groups, thiols and alpha,beta-unsaturated moieties (such as maleimides or dehydroalanine), thiols and alpha-halo amides, carboxylic acids and hydrazides, aldehydes and hydrazides, and ketones and hydrazides. Antagonistic CD28 antibodies can be conjugated to various molecules for the purpose of improving the half-life, solubility, and stability of the protein in aqueous solution. Examples of such molecules include polyethylene glycol (PEG), murine serum albumin (MSA), bovine serum albumin (BSA), and human serum albumin (HSA), among others. For instance, one can conjugate an antagonistic CD28 antibody to carbohydrate moieties in order to evade detection of the antibody or fragment thereof by the immune system of the patient receiving treatment. This process of hyperglycosylation reduces the immunogenicity of therapeutic proteins by sterically inhibiting the interaction of the protein with B cell receptors in circulation. Additionally, antagonistic CD28 antibodies or fragments thereof can be conjugated to molecules that prevent clearance from human serum and improve the pharmacokinetic profile of the antibody. Serum albumin is a globular protein that is the most abundant blood protein in mammals. Serum albumin is produced in the liver and constitutes about half of the blood serum proteins. It is monomeric and soluble in the blood. Some of the most crucial functions of serum albumin include transporting hormones, fatty acids, and other proteins in the body, buffering pH, and maintaining osmotic pressure needed for proper distribution of bodily fluids between blood vessels and body tissues. In some embodiments, serum albumin is MSA or HSA. In some embodiments, MSA or HSA is joined to the N- or C- terminus of an antibody of the disclosure described herein to increase the serum half-life of the antibody. MSA or HSA can be joined, either directly or through a linker, to the N- or C- terminus of an antibody of the disclosure. In some embodiments, an antibody described herein is fused to the N- or C-terminus of a serum albumin through genetic or chemical means, e.g., chemical conjugation. If desired, a linker (e.g., a spacer) can be inserted between the antibody and the serum albumin. In some embodiments, the MSA has the amino acid sequence of UniProt ID NO: Q546G4 (SEQ ID NO: 70), or an amino acid sequence that is at least 85% identical (e.g., at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 70, shown below: MKWVTFLLLLFVSGSAFSRGVFRREAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQ KCSY DEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCT KQEP ERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYA PELLY YAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAF KAWAV ARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISS KLQ TCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLY EYSR RHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNC DLYE KLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDY LSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDI CTL PEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEG PNLV TRCKDALA (SEQ ID NO: 70) In some embodiments, the HSA has the amino acid sequence of UniProt ID NO: P02768 (SEQ ID NO: 71), or an amino acid sequence that is at least 85% identical (e.g., at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 71, shown below: MKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYL QQCPF EDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMAD CCAKQEP ERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYF YAPELLF FAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAV ARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDS ISSKLK ECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGM FLYEYAR RHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQ NCELFE QLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCA EDYLSVV LNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFH ADICTL SEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAE EGKKLV AASQAALGL (SEQ ID NO: 71) On of ordinary skill in the art would recognize that the first 25 amino acids of SEQ ID NO: 71 represent a signal sequence and that in some embodiments this signal sequence may be omitted. In some embodiments, the HSA has the amino acid sequence of SEQ ID NO: 157, or an amino acid sequence that is at least 85% identical (e.g., at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 157, shown below: AHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVA DESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKD DNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRY KAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAW AVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQ DSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEA KDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDE FKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNL GKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVN RRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPK ATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 157) Antagonistic CD28 antibodies can be covalently appended directly to another molecule by chemical conjugation as described. Alternatively, fusion proteins containing antagonistic CD28 antibodies and fragments thereof can be expressed recombinantly from a cell (e.g., a eukaryotic cell or prokaryotic cell). This can be accomplished, for example, by incorporating a polynucleotide encoding the fusion protein into the genome of a cell (e.g., using techniques described herein or known in the art). Optionally, antibodies and fragments thereof described herein can be joined to a second molecule by forming a covalent bond between the antibody and a linker. This linker can then be subsequently conjugated to another molecule, or the linker can be conjugated to another molecule prior to ligation to the antagonistic CD28 antibody or fragment thereof. Examples of linkers that can be used for the formation of a conjugate include polypeptide linkers, such as those that contain naturally occurring or non-naturally occurring amino acids. In some embodiments, it may be desirable to include D-amino acids in the linker, as these residues are not present in naturally-occurring proteins and are thus more resistant to degradation by endogenous proteases. Fusion proteins containing polypeptide linkers can be made using chemical synthesis techniques, such as those described herein, or through recombinant expression of a polynucleotide encoding the fusion protein in a cell (e.g., a prokaryotic or eukaryotic cell). Linkers can be prepared using a variety of strategies that are well known in the art, and depending on the reactive components of the linker, can be cleaved by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012). For example, in some embodiments, the antibody is covalently bound to the HSA peptide, such as by way of a peptidic linker comprising one or more glycine and/or serine residues. In some embodiments, the peptidic linker is represented by the formula (G_xS)_y, wherein each x is, independently, an integer of from 1 to 10 and y is an integer of from 1 to 5. In some embodiments, each x is, independently, an integer of from 1 to 5. In some embodiments, each x is 4. In some embodiments, the peptidic linker is GGGGS (SEQ ID NO: 72), GGGGSGGGGS (SEQ ID NO: 73), or GGGGSGGGGSGGGGS (SEQ ID NO: 74). In some embodiments, the C-terminus of the antibody is bound to the N-terminus of the HSA or MSA peptide. In some embodiments, the N-terminus of the antibody is bound to the C-terminus of the HSA or MSA peptide. In some embodiments, the C-terminus of the antibody is bound to the N-terminus of the HSA peptide. In some embodiments, the N- terminus of the antibody is bound to the C-terminus of the HSA peptide. Any of the disclosed anti-CD28 VHH, antibodies, antigen-binding fragments, or binding proteins can be linked to an albumin protein (e.g., HSA) to improve half-life in vivo. For example, SEQ ID NO: 81 comprises the anti-CD28 VHH of SEQ ID NO: 41 and a has of SEQ ID NO: 157: EVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMGWYRQAPGKQRELVAAITSGGSAT YEDSVKGRFTISRDNSKNTVYLQMNSLRAEDTAIYYCAADNWGIVRWRAPDYWGQGTLV TVSSGGGGSGGGGSGGGGSAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVK LVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNEC FLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYK AAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQ RFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKP LLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYS VVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKF QNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVL HEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKK QTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 81). In some embodiments, when this sequence is expressed in vivo, it can optionally include a leader sequence or signal peptide that is cleaved off of the mature antibody during post-translational processing, such as, for example, METPAQLLFLLLLWLPDTTG (SEQ ID NO: 75). For example, SEQ ID NO: 158 comprises the leader sequence of SEQ ID NO: 75, the anti-CD28 VHH of SEQ ID NO: 41 and the HSA sequence of SEQ ID NO: 157: METPAQLLFLLLLWLPDTTGEVQLVESGGGLVQPGGSLRLSCAASGSVFSGNVMG WYRQAPGKQRELVAAITSGGSATYEDSVKGRFTISRDNSKNTVYLQMNSLRAEDTAIYYC AADNWGIVRWRAPDYWGQGTLVTVSSGGGGSGGGGSGGGGSAHKSEVAHRFKDLGEE NFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVA TLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKK YLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRL KCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRA DLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLV EEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHP EAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKE FNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKAD DKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 158). Nucleic Acids as Agents for Delivering Antagonistic CD28 Antibodies The compositions of the disclosure can be administered not only as antibodies but also in the form of nucleic acids. This section provides exemplary nucleic acids that may be used to deliver antibodies of the disclosure to a subject (e.g., a subject suffering from an autoimmune disease or GVHD described herein). These nucleic acids (e.g., RNAs, such as mRNAs) may be used as therapeutic agents to express antibodies of the disclosure as a therapy to treat a target disease. The nucleic acid molecules of the disclosure may include one or more alterations. Herein, in a nucleotide, nucleoside, or polynucleotide (such as the nucleic acids of the disclosure (e.g., an mRNA or an oligonucleotide)), the terms “alteration” or, as appropriate, “alternative” refer to alteration with respect to A, G, U or C ribonucleotides. The alterations may be various distinct alterations. In some embodiments, where the nucleic acid is an mRNA, the coding region, the flanking regions, and/or the terminal regions may contain one, two, or more (optionally different) nucleoside or nucleotide alterations. In some embodiments, an alternative polynucleotide introduced to a cell may exhibit reduced degradation in the cell, as compared to an unaltered polynucleotide. The polynucleotides can include any useful alteration, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage, or to the phosphodiester backbone). In certain embodiments, alterations (e.g., one or more alterations) are present in each of the sugar and the internucleoside linkage. Alterations according to the present disclosure may be alterations of ribonucleic acids (RNAs) to deoxyribonucleic acids (DNAs) (e.g., the substitution of the 2’OH of the ribofuranosyl ring to 2’H), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs) or hybrids thereof. Additional alterations are described herein. In certain embodiments, it may be desirable for a nucleic acid molecule introduced into the cell to be degraded intracellularly. For example, degradation of a nucleic acid molecule may be preferable if precise timing of protein production is desired. Thus, in some embodiments, the disclosure provides an alternative nucleic acid molecule containing a degradation domain, which is capable of being acted on in a directed manner within a cell. The polynucleotides can optionally include other agents (e.g., RNAi-inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers, vectors, etc.). In some embodiments, the polynucleotides may include one or more messenger RNAs (mRNAs) having one or more alternative nucleoside or nucleotides (i.e., mRNA molecules). In some embodiments, the polynucleotides may include one or more oligonucleotides having one or more alternative nucleoside or nucleotides. In some embodiments, a composition of the disclosure includes an mRNA and/or one or more oligonucleotides having one or more alternative nucleoside or nucleotides. Modified nucleic acids In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, 5- methoxyuracil, or the like. In some embodiments, the mRNA is a uracil-modified sequence comprising an ORF encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein, wherein the mRNA comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, or 5-methoxyuracil. In certain aspects of the present disclosure, when the modified uracil base is connected to a ribose sugar, as it is in polynucleotides, the resulting modified nucleoside or nucleotide is referred to as modified uridine. In some embodiments, uracil in the polynucleotide is at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least 90%, at least 95%, at least 99%, or about 100% modified uracil. In some embodiments, uracil in the polynucleotide is at least 95% modified uracil. In some embodiments, uracil in the polynucleotide is 100% modified uracil. In embodiments where uracil in the polynucleotide is at least 95% modified uracil overall uracil content can be adjusted such that an mRNA provides suitable protein expression levels while inducing little to no immune response. In some embodiments, the uracil content of the ORF is between about 100% and about 150%, between about 100% and about 110%, between about 105% and about 115%, between about 110% and about 120%, between about 115% and about 125%, between about 120% and about 130%, between about 125% and about 135%, between about 130% and about 140%, between about 135% and about 145%, between about 140% and about 150% of the theoretical minimum uracil content in the corresponding wild-type ORF (%U_TM). In other embodiments, the uracil content of the ORF is between about 121% and about 136% or between 123% and 134% of the %U_TM. In some embodiments, the uracil content of the ORF encoding an anti-CD28 polypeptide is about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% of the %U_TM. In this context, the term "uracil" can refer to modified uracil and/or naturally occurring uracil. In some embodiments, the uracil content in the ORF of the mRNA encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein is less than about 30%, about 25%, about 20%, about 15%, or about 10% of the total nucleobase content in the ORF. In some embodiments, the uracil content in the ORF is between about 10% and about 20% of the total nucleobase content in the ORF. In other embodiments, the uracil content in the ORF is between about 10% and about 25% of the total nucleobase content in the ORF. In some embodiments, the uracil content in the ORF of the mRNA encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein is less than about 20% of the total nucleobase content in the open reading frame. In this context, the term "uracil" can refer to modified uracil and/or naturally occurring uracil. In further embodiments, the ORF of the mRNA encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein having modified uracil and adjusted uracil content has increased Cytosine (C), Guanine (G), or Guanine/Cytosine (G/C) content (absolute or relative). In some embodiments, the overall increase in C, G, or G/C content (absolute or relative) of the ORF is at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100% relative to the G/C content (absolute or relative) of the wild-type ORF. In some embodiments, the G, the C, or the G/C content in the ORF is less than about 100%, less than about 90%, less than about 85%, or less than about 80% of the theoretical maximum G, C, or G/C content of the corresponding wild type nucleotide sequence encoding the anti-CD28 polypeptide (%G_TMX; %C_TMX, or %G/C_TMX). In some embodiments, the increases in G and/or C content (absolute or relative) described herein can be conducted by replacing synonymous codons with low G, C, or G/C content with synonymous codons having higher G, C, or G/C content. In other embodiments, the increase in G and/or C content (absolute or relative) is conducted by replacing a codon ending with U with a synonymous codon ending with G or C. In further embodiments, the ORF of the mRNA encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein comprises modified uracil and has an adjusted uracil content containing less uracil pairs (UU) and/or uracil triplets (UUU) and/or uracil quadruplets (UUUU) than the corresponding wild-type nucleotide sequence encoding the anti-CD28 polypeptide. In some embodiments, the ORF of the mRNA encoding encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein contains no uracil pairs and/or uracil triplets and/or uracil quadruplets. In some embodiments, uracil pairs and/or uracil triplets and/or uracil quadruplets are reduced below a certain threshold, e.g., no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 occurrences in the ORF of the mRNA encoding the ant-CD28 polypeptide. In a particular embodiment, the ORF of the mRNA encoding the anti- CD28 polypeptide of the present disclosure contains less than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-phenylalanine uracil pairs and/or triplets. In some embodiments, the ORF of the mRNA encoding the anti-CD28 polypeptide contains no non-phenylalanine uracil pairs and/or triplets. In further embodiments, the ORF of the mRNA encoding encoding an anti- CD28 antibody, antigen-binding fragment, or binding protein as disclosed herein comprises modified uracil and has an adjusted uracil content containing fewer uracil- rich clusters than the corresponding wild-type nucleotide sequence encoding the anti-CD28 polypeptide. In some embodiments, the ORF of the mRNA encoding the anti-CD28 polypeptide of the present disclosure contains uracil-rich clusters that are shorter in length than corresponding uracil-rich clusters in the corresponding wild- type nucleotide sequence encoding the anti-CD28 polypeptide. In further embodiments, alternative lower frequency codons are employed. At least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% of the codons in the anti-CD28 polypeptide–encoding ORF of the modified uracil- comprising mRNA are substituted with alternative codons, each alternative codon having a codon frequency lower than the codon frequency of the substituted codon in the synonymous codon set. The ORF also has adjusted uracil content, as described above. In some embodiments, at least one codon in the ORF of the mRNA encoding the ant-CD28 polypeptide is substituted with an alternative codon having a codon frequency lower than the codon frequency of the substituted codon in the synonymous codon set. According to Aduri et al., (Aduri, R. et al., AMBER force field parameters for the naturally occurring modified nucleosides in RNA. Journal of Chemical Theory and Computation.2006.3(4):1464-75), there are 107 naturally occurring nucleosides, including 1-methyladenosine, 2-methylthio-N6-hydroxynorvalyl carbamoyladenosine, 2-methyladenosine, 2-O-ribosylphosphate adenosine, N6- methyl-N6-threonylcarbamoyladenosine, N6-acetyladenosine, N6- glycinylcarbamoyladenosine, N6-isopentenyladenosine, N6-methyladenosine, N6- threonylcarbamoyladenosine, N6,N6-dimethyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, N6-hydroxynorvalylcarbamoyladenosine, 1,2-O- dimethyladenosine, N6,2-O-dimethyladenosine, 2-O-methyladenosine, N6,N6,O-2- trimethyladenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, 2- methylthio-N6-methyladenosine, 2-methylthio-N6-isopentenyladenosine, 2- methylthio-N6-threonyl carbamoyladenosine, 2-thiocytidine, 3-methylcytidine , N4- acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-methylcytidine, 5- hydroxymethylcytidine, lysidine, N4-acetyl-2-O-methylcytidine, 5-formyl-2-O- methylcytidine, 5,2-O-dimethylcytidine, 2-O-methylcytidine, N4,2-O-dimethylcytidine, N4,N4,2-O-trimethylcytidine, 1-methylguanosine, N2,7-dimethylguanosine, N2- methylguanosine, 2-O-ribosylphosphate guanosine, 7-methylguanosine, under modified hydroxywybutosine, 7-aminomethyl-7-deazaguanosine, 7-cyano-7- deazaguanosine, N2,N2-dimethylguanosine, 4-demethylwyosine, epoxyqueuosine, hydroxywybutosine, isowyosine, N2,7,2-O-trimethylguanosine, N2,2-O- dimethylguanosine, 1,2-O-dimethylguanosine, 2-O-methylguanosine, N2,N2,2-O- trimethylguanosine, N2,N2,7-trimethylguanosine, peroxywybutosine, galactosyl- queuosine, mannosyl-queuosine, queuosine, archaeosine, wybutosine, methylwyosine, wyosine, 2-thiouridine, 3-(3-amino-3-carboxypropyl)uridine, 3- methyluridine, 4-thiouridine, 5-methyl-2-thiouridine, 5-methylaminomethyluridine, 5- carboxymethyluridine, 5-carboxymethylaminomethyluridine, 5-hydroxyuridine, 5- methyluridine, 5-taurinomethyluridine, 5-carbamoylmethyluridine, 5- (carboxyhydroxymethyl)uridine methyl ester, dihydrouridine, 5-methyldihydrouridine, 5-methylaminomethyl-2-thiouridine, 5-(carboxyhydroxymethyl)uridine, 5- (isopentenylaminomethyl)uridine, 5-(isopentenylaminomethyl)-2-thiouridine, 3,2-O- dimethyluridine, 5-carboxymethylaminomethyl-2-O-methyluridine, 5- carbamoylmethyl-2-O-methyluridine, 5-methoxycarbonylmethyl-2-O-methyluridine, 5-(isopentenylaminomethyl)-2-O-methyluridine, 5,2-O-dimethyluridine, 2-O- methyluridine, 2-thio-2-O-methyluridine, uridine 5-oxyacetic acid, 5- methoxycarbonylmethyluridine, uridine 5-oxyacetic acid methyl ester, 5- methoxyuridine, 5-aminomethyl-2-thiouridine, 5-carboxymethylaminomethyl-2- thiouridine, 5-methylaminomethyl-2-selenouridine, 5-methoxycarbonylmethyl-2- thiouridine, 5-taurinomethyl-2-thiouridine, pseudouridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine, 2-O- methylpseudouridine, inosine, 1-methylinosine, 1,2-O-dimethylinosine, and 2-O- methylinosine. Each of these may be components of nucleic acids of the present disclosure. Methods for Modifying Polynucleotides The disclosure includes modified polynucleotides comprising a polynucleotide described herein (e.g., a polynucleotide, e.g. mRNA, comprising a nucleotide sequence encoding an anti-CD28 polypeptide). The modified polynucleotides can be chemically modified and/or structurally modified. When the polynucleotides of the present disclosure are chemically and/or structurally modified the polynucleotides can be referred to as "modified polynucleotides." The present disclosure provides for modified nucleosides and nucleotides of a polynucleotide (e.g., RNA polynucleotides, such as mRNA polynucleotides) encoding an anti-CD28 polypeptide. A "nucleoside" refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as "nucleobase"). A “nucleotide" refers to a nucleoside including a phosphate group. Modified nucleotides can be synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Polynucleotides can comprise a region or regions of linked nucleosides. Such regions can have variable backbone linkages. The linkages can be standard phosphodiester linkages, in which case the polynucleotides would comprise regions of nucleotides. The modified polynucleotides disclosed herein can comprise various distinct modifications. In some embodiments, the modified polynucleotides contain one, two, or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified polynucleotide, introduced to a cell can exhibit one or more desirable properties, e.g., improved protein expression, reduced immunogenicity, or reduced degradation in the cell, as compared to an unmodified polynucleotide. In some embodiments, a polynucleotide of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide) is structurally modified. As used herein, a "structural" modification is one in which two or more linked nucleosides are inserted, deleted, duplicated, inverted or randomized in a polynucleotide without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to effect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide "ATCG" can be chemically modified to "AT-5meC-G". The same polynucleotide can be structurally modified from "ATCG" to "ATCCCG". Here, the dinucleotide "CC" has been inserted, resulting in a structural modification to the polynucleotide. Therapeutic compositions of the present disclosure comprise, in some embodiments, at least one nucleic acid (e.g., RNA) having an open reading frame encoding an anti-CD28 polypeptide disclosed herein, wherein the nucleic acid comprises nucleotides and/or nucleosides that can be standard (unmodified) or modified as is known in the art. In some embodiments, nucleotides and nucleosides of the present disclosure comprise modified nucleotides or nucleosides. Such modified nucleotides and nucleosides can be naturally-occurring modified nucleotides and nucleosides or non-naturally occurring modified nucleotides and nucleosides. Such modifications can include those at the sugar, backbone, or nucleobase portion of the nucleotide and/or nucleoside as are recognized in the art. In some embodiments, a naturally-occurring modified nucleotide or nucleotide of the disclosure is one as is generally known or recognized in the art. Non-limiting examples of such naturally occurring modified nucleotides and nucleotides can be found, inter alia, in the widely recognized MODOMICS database. In some embodiments, a non-naturally occurring modified nucleotide or nucleoside of the disclosure is one as is generally known or recognized in the art. Non-limiting examples of such non-naturally occurring modified nucleotides and nucleosides can be found, inter alia, in published US Application Nos. PCT/US2012/058519; PCT/US2013/075177; PCT/US2014/058897; PCT/US2014/058891; PCT/US2014/070413; PCT/US2015/36773; PCT/US2015/36759; PCT/US2015/36771; or PCT/IB2017/051367 all of which are incorporated by reference herein. In some embodiments, at least one RNA (e.g., mRNA) of the present disclosure is not chemically modified and comprises the standard ribonucleotides consisting of adenosine, guanosine, cytosine and uridine. In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard nucleoside residues such as those present in transcribed RNA (e.g. A, G, C, or U). In some embodiments, nucleotides and nucleosides of the present disclosure comprise standard deoxyribonucleosides such as those present in DNA (e.g. dA, dG, dC, or dT). Hence, nucleic acids of the disclosure (e.g., DNA nucleic acids and RNA nucleic acids, such as mRNA nucleic acids) can comprise standard nucleotides and nucleosides, naturally-occurring nucleotides and nucleosides, non-naturally- occurring nucleotides and nucleosides, or any combination thereof. Nucleic acids of the disclosure (e.g., RNA nucleic acids, such as mRNA nucleic acids), in some embodiments, comprise various (more than one) different types of standard and/or modified nucleotides and nucleosides. In some embodiments, a particular region of a nucleic acid contains one, two or more (optionally different) types of standard and/or modified nucleotides and nucleosides. In some embodiments, a modified RNA nucleic acid (e.g., a modified mRNA nucleic acid), introduced to a cell or organism, exhibits reduced degradation in the cell or organism, respectively, relative to an unmodified nucleic acid comprising standard nucleotides and nucleosides. In some embodiments, a modified RNA nucleic acid (e.g., a modified mRNA nucleic acid), introduced into a cell or organism, may exhibit reduced immunogenicity in the cell or organism, respectively (e.g., a reduced innate response) relative to an unmodified nucleic acid comprising standard nucleotides and nucleosides. Nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids), in some embodiments, comprise non-natural modified nucleotides that are introduced during synthesis or post-synthesis of the nucleic acids to achieve desired functions or properties. The modifications may be present on internucleotide linkages, purine or pyrimidine bases, or sugars. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a nucleic acid may be chemically modified. The present disclosure provides for modified nucleosides and nucleotides of a nucleic acid (e.g., RNA nucleic acids, such as mRNA nucleic acids). A “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). A “nucleotide” refers to a nucleoside, including a phosphate group. Modified nucleotides may by synthesized by any useful method, such as, for example, chemically, enzymatically, or recombinantly, to include one or more modified or non-natural nucleosides. Nucleic acids can comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages can be standard phosphodiester linkages, in which case the nucleic acids would comprise regions of nucleotides. Modified nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non- standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures, such as, for example, in those nucleic acids having at least one chemical modification. One example of such non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil. Any combination of base/sugar or linker may be incorporated into nucleic acids of the present disclosure. In some embodiments, modified nucleobases in nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) comprise N1-methyl-pseudouridine (m1ψ), 1-ethyl-pseudouridine (e1ψ), 5-methoxy-uridine (mo5U), 5-methyl-cytidine (m5C), and/or pseudouridine (ψ). In some embodiments, modified nucleobases in nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) comprise 5- methoxymethyl uridine, 5-methylthio uridine, 1-methoxymethyl pseudouridine, 5- methyl cytidine, and/or 5-methoxy cytidine. In some embodiments, the polyribonucleotide includes a combination of at least two (e.g., 2, 3, 4 or more) of any of the aforementioned modified nucleobases, including but not limited to chemical modifications. In some embodiments, a RNA nucleic acid of the disclosure comprises N1- methyl-pseudouridine (m1ψ) substitutions at one or more or all uridine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises N1- methyl-pseudouridine (m1ψ) substitutions at one or more or all uridine positions of the nucleic acid and 5-methyl cytidine substitutions at one or more or all cytidine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises pseudouridine (ψ) substitutions at one or more or all uridine positions of the nucleic acid and 5-methyl cytidine substitutions at one or more or all cytidine positions of the nucleic acid. In some embodiments, a RNA nucleic acid of the disclosure comprises uridine at one or more or all uridine positions of the nucleic acid. In some embodiments, nucleic acids (e.g., RNA nucleic acids, such as mRNA nucleic acids) are uniformly modified (e.g., fully modified, modified throughout the entire sequence) for a particular modification. For example, a nucleic acid can be uniformly modified with N1-methyl-pseudouridine, meaning that all uridine residues in the mRNA sequence are replaced with N1-methyl-pseudouridine. Similarly, a nucleic acid can be uniformly modified for any type of nucleoside residue present in the sequence by replacement with a modified residue such as those set forth above. The nucleic acids of the present disclosure may be partially or fully modified along the entire length of the molecule. For example, one or more or all or a given type of nucleotide (e.g., purine or pyrimidine, or any one or more or all of A, G, U, C) may be uniformly modified in a nucleic acid of the disclosure, or in a predetermined sequence region thereof (e.g., in the mRNA including or excluding the polyA tail). In some embodiments, all nucleotides X in a nucleic acid of the present disclosure (or in a sequence region thereof) are modified nucleotides, wherein X may be any one of nucleotides A, G, U, C, or any one of the combinations A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C or A+G+C. The nucleic acid may contain from about 1% to about 100% modified nucleotides (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e., any one or more of A, G, U or C) or any intervening percentage (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 80% to 100%, from 90% to 95%, from 90% to 100%, and from 95% to 100%). It will be understood that any remaining percentage is accounted for by the presence of unmodified A, G, U, or C. The nucleic acids may contain at a minimum 1% and at maximum 100% modified nucleotides, or any intervening percentage, such as at least 5% modified nucleotides, at least 10% modified nucleotides, at least 25% modified nucleotides, at least 50% modified nucleotides, at least 80% modified nucleotides, or at least 90% modified nucleotides. For example, the nucleic acids may contain a modified pyrimidine such as a modified uracil or cytosine. In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the uracil in the nucleic acid is replaced with a modified uracil (e.g., a 5-substituted uracil). The modified uracil can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). In some embodiments, at least 5%, at least 10%, at least 25%, at least 50%, at least 80%, at least 90% or 100% of the cytosine in the nucleic acid is replaced with a modified cytosine (e.g., a 5-substituted cytosine). The modified cytosine can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures). Nucleosides containing modified sugars The alternative nucleosides and nucleotides (e.g., building block molecules), which may be incorporated into a polynucleotide (e.g., RNA or mRNA, as described herein), can be altered on the sugar of the ribonucleic acid. For example, the 2′ hydroxyl group (OH) can be modified or replaced with a number of different substituents. Exemplary substitutions at the 2′-position include, but are not limited to, H, halo, optionally substituted C_1-6 alkyl; optionally substituted C_1-6 alkoxy; optionally substituted C_6-10 aryloxy; optionally substituted C_3-8 cycloalkyl; optionally substituted C_3-8 cycloalkoxy; optionally substituted C_6-10 aryloxy; optionally substituted C_6-10 aryl-C_1-6 alkoxy, optionally substituted C_1-12 (heterocyclyl)oxy; a sugar (e.g., ribose, pentose, or any described herein); a polyethyleneglycol (PEG), - O(CH₂CH₂O)_nCH₂CH₂OR, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from 1 to 20, from 2 to 4, from 2 to 8, from 2 to 10, from 2 to 16, from 2 to 20, from 4 to 8, from 4 to 10, from 4 to 16, and from 4 to 20); “locked” nucleic acids (LNA) in which the 2′-hydroxyl is connected by a C_1-6 alkylene or C_1-6 heteroalkylene bridge to the 4’-carbon of the same ribose sugar, where exemplary bridges included methylene, propylene, ether, or amino bridges; aminoalkyl, as defined herein; aminoalkoxy, as defined herein; amino as defined herein; and amino acid, as defined herein Generally, RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary, non-limiting alternative nucleotides include replacement of the oxygen in ribose (e.g., with S, Se, or alkylene, such as methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone); multicyclic forms (e.g., tricyclo; and “unlocked” forms, such as glycol nucleic acid (GNA) (e.g., R-GNA or S-GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), threose nucleic acid (TNA, where ribose is replace with α-L-threofuranosyl-(3′→2′)), and peptide nucleic acid (PNA, where 2-amino-ethyl-glycine linkages replace the ribose and phosphodiester backbone). The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a polynucleotide molecule can include nucleotides containing, e.g., arabinose, as the sugar. Alterations on the nucleobase The present disclosure provides for alternative nucleosides and nucleotides. As described herein “nucleoside” is defined as a compound containing a sugar molecule (e.g., a pentose or ribose) or derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). As described herein, “nucleotide” is defined as a nucleoside including a phosphate group. Exemplary non-limiting alterations include an amino group, a thiol group, an alkyl group, a halo group, or any described herein. The alternative nucleotides may by synthesized by any useful method, as described herein (e.g., chemically, enzymatically, or recombinantly to include one or more alternative or alternative nucleosides). In some embodiments, a nucleic acid of the disclosure (e.g., an mRNA or an oligonucleotide) includes one or more 2’-OMe nucleotides, 2’-methoxyethyl nucleotides (2’-MOE nucleotides), 2’-F nucleotide, 2’-NH2 nucleotide, 2’fluoroarabino nucleotides (FANA nucleotides), locked nucleic acid nucleotides (LNA nucleotides), or 4’-S nucleotides. The alternative nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, and guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or alternative nucleotides including non- standard or alternative bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. One example of such non-standard base pairing is the base pairing between the alternative nucleotide inosine and adenine, cytosine, or uracil. The alternative nucleosides and nucleotides can include an alternative nucleobase. Examples of nucleobases found in RNA include, but are not limited to, adenine, guanine, cytosine, and uracil. Examples of nucleobase found in DNA include, but are not limited to, adenine, guanine, cytosine, and thymine. These nucleobases can be altered or wholly replaced to provide polynucleotide molecules having enhanced properties (e.g., resistance to nucleases and stability), and these properties may manifest through disruption of the binding of a major groove binding partner. In some embodiments, the alternative nucleobase is an alternative uracil. Exemplary nucleobases and nucleosides having an alternative uracil include pseudouridine (ψ), pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio- 5-aza-uridine, 2-thio-uridine (s²U), 4-thio-uridine (s⁴U), 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxy-uridine (ho⁵U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5- iodo-uridineor 5-bromo-uridine), 3-methyl-uridine (m³U), 5-methoxy-uridine (mo⁵U), uridine 5-oxyacetic acid (cmo⁵U), uridine 5-oxyacetic acid methyl ester (mcmo⁵U), 5- carboxymethyl-uridine (cm⁵U), 1-carboxymethyl-pseudouridine, 5- carboxyhydroxymethyl-uridine (chm⁵U), 5-carboxyhydroxymethyl-uridine methyl ester (mchm⁵U), 5-methoxycarbonylmethyl-uridine (mcm⁵U), 5- methoxycarbonylmethyl-2-thio-uridine (mcm⁵s²U), 5-aminomethyl-2-thio-uridine (nm⁵s²U), 5-methylaminomethyl-uridine (mnm⁵U), 5-methylaminomethyl-2-thio- uridine (mnm⁵s²U), 5-methylaminomethyl-2-seleno-uridine (mnm⁵se²U), 5- carbamoylmethyl-uridine (ncm⁵U), 5-carboxymethylaminomethyl-uridine (cmnm⁵U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm⁵s²U), 5-propynyl-uridine, 1- propynyl-pseudouridine, 5-taurinomethyl-uridine (τm⁵U), 1-taurinomethyl- pseudouridine, 5-taurinomethyl-2-thio-uridine(τm⁵s²U), 1-taurinomethyl-4-thio- pseudouridine, 5-methyl-uridine (m⁵U, i.e., having the nucleobase deoxythymine), 1- methyl-pseudouridine (m¹ψ), 5-methyl-2-thio-uridine (m⁵s²U), 1-methyl-4-thio- pseudouridine (m¹s⁴ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m³ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1- methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6- dihydrouridine, 5-methyl-dihydrouridine (m⁵D), 2-thio-dihydrouridine, 2-thio- dihydropseudouridine, 2-methoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy- pseudouridine, 4-methoxy-2-thio-pseudouridine, N1-methyl-pseudouridine, 3-(3- amino-3-carboxypropyl)uridine (acp³U), 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine (acp³ ψ), 5-(isopentenylaminomethyl)uridine (inm⁵U), 5-(isopentenylaminomethyl)-2-thio-uridine (inm⁵s²U), α-thio-uridine, 2′-O-methyl- uridine (Um), 5,2′-O-dimethyl-uridine (m⁵Um), 2′-O-methyl-pseudouridine (ψm), 2- thio-2′-O-methyl-uridine (s²Um), 5-methoxycarbonylmethyl-2′-O-methyl-uridine (mcm⁵Um), 5-carbamoylmethyl-2′-O-methyl-uridine (ncm⁵Um), 5- carboxymethylaminomethyl-2′-O-methyl-uridine (cmnm⁵Um), 3,2′-O-dimethyl-uridine (m³Um), and 5-(isopentenylaminomethyl)-2′-O-methyl-uridine (inm⁵Um), 1-thio- uridine, deoxythymidine, 2’-F-ara-uridine, 2’-F-uridine, 2’-OH-ara-uridine, 5-(2- carbomethoxyvinyl) uridine, and 5-[3-(1-E-propenylamino)uridine. In preferred embodiments, the nucleic acid is modified to contain 1- methylpseudouridine (m¹ψ) in lieu of uridine at each instance. In some embodiments, the alternative nucleobase is an alternative cytosine. Exemplary nucleobases and nucleosides having an alternative cytosine include 5- aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine (m³C), N4-acetyl- cytidine (ac⁴C), 5-formyl-cytidine (f⁵C), N4-methyl-cytidine (m⁴C), 5-methyl-cytidine (m⁵C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm⁵C), 1- methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s²C), 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl- pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza- pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio- zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4- methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, lysidine (k₂C), α-thio-cytidine, 2′-O-methyl-cytidine (Cm), 5,2′-O-dimethyl-cytidine (m⁵Cm), N4- acetyl-2′-O-methyl-cytidine (ac⁴Cm), N4,2′-O-dimethyl-cytidine (m⁴Cm), 5-formyl-2′- O-methyl-cytidine (f⁵Cm), N4,N4,2′-O-trimethyl-cytidine (m⁴ ₂Cm), 1-thio-cytidine, 2’- F-ara-cytidine, 2’-F-cytidine, and 2’-OH-ara-cytidine. In some embodiments, the alternative nucleobase is an alternative adenine. Exemplary nucleobases and nucleosides having an alternative adenine include 2- amino-purine, 2, 6-diaminopurine, 2-amino-6-halo-purine (e.g., 2-amino-6-chloro- purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8-azido- adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7- deaza-8-aza-2-amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6- diaminopurine, 1-methyl-adenosine (m¹A), 2-methyl-adenine (m²A), N6-methyl- adenosine (m⁶A), 2-methylthio-N6-methyl-adenosine (ms²m⁶A), N6-isopentenyl- adenosine (i⁶A), 2-methylthio-N6-isopentenyl-adenosine (ms²i⁶A), N6-(cis- hydroxyisopentenyl)adenosine (io⁶A), 2-methylthio-N6-(cis- hydroxyisopentenyl)adenosine (ms²io⁶A), N6-glycinylcarbamoyl-adenosine (g⁶A), N6-threonylcarbamoyl-adenosine (t⁶A), N6-methyl-N6-threonylcarbamoyl-adenosine (m⁶t⁶A), 2-methylthio-N6-threonylcarbamoyl-adenosine (ms²g⁶A), N6,N6-dimethyl- adenosine (m⁶ ₂A), N6-hydroxynorvalylcarbamoyl-adenosine (hn⁶A), 2-methylthio- N6-hydroxynorvalylcarbamoyl-adenosine (ms²hn⁶A), N6-acetyl-adenosine (ac⁶A), 7- methyl-adenine, 2-methylthio-adenine, 2-methoxy-adenine, α-thio-adenosine, 2′-O- methyl-adenosine (Am), N6,2′-O-dimethyl-adenosine (m⁶Am), N6,N6,2′-O-trimethyl- adenosine (m⁶ ₂Am), 1,2′-O-dimethyl-adenosine (m¹Am), 2′-O-ribosyladenosine (phosphate) (Ar(p)), 2-amino-N6-methyl-purine, 1-thio-adenosine, 8-azido- adenosine, 2’-F-ara-adenosine, 2’-F-adenosine, 2’-OH-ara-adenosine, and N6-(19- amino-pentaoxanonadecyl)-adenosine. In some embodiments, the alternative nucleobase is an alternative guanine. Exemplary nucleobases and nucleosides having an alternative guanine include inosine (I), 1-methyl-inosine (m¹I), wyosine (imG), methylwyosine (mimG), 4- demethyl-wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o₂yW), hydroxywybutosine (OhyW), undermodified hydroxywybutosine (OhyW*), 7-deaza-guanosine, queuosine (Q), epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl-queuosine (manQ), 7-cyano-7-deaza- guanosine (preQ₀), 7-aminomethyl-7-deaza-guanosine (preQ1), archaeosine (G⁺), 7- deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7- deaza-8-aza-guanosine, 7-methyl-guanosine (m⁷G), 6-thio-7-methyl-guanosine, 7- methyl-inosine, 6-methoxy-guanosine, 1-methyl-guanosine (m¹G), N2-methyl- guanosine (m²G), N2,N2-dimethyl-guanosine (m² ₂G), N2,7-dimethyl-guanosine (m^2,7G), N2, N2,7-dimethyl-guanosine (m^2,2,7G), 8-oxo-guanosine, 7-methyl-8-oxo- guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl- 6-thio-guanosine, α-thio-guanosine, 2′-O-methyl-guanosine (Gm), N2-methyl-2′-O- methyl-guanosine (m²Gm), N2,N2-dimethyl-2′-O-methyl-guanosine (m² ₂Gm), 1- methyl-2′-O-methyl-guanosine (m¹Gm), N2,7-dimethyl-2′-O-methyl-guanosine (m^2,7Gm), 2′-O-methyl-inosine (Im), 1,2′-O-dimethyl-inosine (m¹Im), 2′-O- ribosylguanosine (phosphate) (Gr(p)) , 1-thio-guanosine, O6-methyl-guanosine, 2’-F- ara-guanosine, and 2’-F-guanosine. The nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine, or pyrimidine analog. For example, the nucleobase can each be independently selected from adenine, cytosine, guanine, uracil, or hypoxanthine. In some embodiments, the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo[3,4- d]pyrimidines, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl, and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2- thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8- thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3-deazaadenine, pyrazolo[3,4-d]pyrimidine, imidazo[1,5-a]1,3,5 triazinones, 9- deazapurines, imidazo[4,5-d]pyrazines, thiazolo[4,5-d]pyrimidines, pyrazin-2-ones, 1,2,4-triazine, pyridazine; and 1,3,5 triazine. When the nucleotides are depicted using the shorthand A, G, C, T or U, each letter refers to the representative base and/or derivatives thereof (e.g., A includes adenine or adenine analogs (e.g., 7- deaza adenine)). In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-trifluoromethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uracil, uracil, 5-hydroxymethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uracil, uracil, 5-bromo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-iodo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-methoxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-ethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-phenyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-ethnyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, N4-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-fluoro-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, N4-acetyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, pseudoisocytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-formyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-aminoallyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uracil, uracil, 5-carboxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl- pseudouracil, uracil, 5-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1- methyl-pseudouracil, uracil, 5-trifluoromethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-hydroxymethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-bromo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-iodo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-methoxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-ethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-phenyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-ethnyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, N4-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-fluoro-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, N4-acetyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, pseudoisocytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-formyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-aminoallyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouracil, uracil, 5-carboxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-trifluoromethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uridine, uridine, 5-hydroxymethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uridine, uridine, 5-bromo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uridine, uridine, 5-iodo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5-methoxy-uridine, uridine, 5-methoxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-ethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-phenyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-ethnyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, N4-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-fluoro-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, N4-acetyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, pseudoisocytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-formyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-aminoallyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 5- methoxy-uridine, uridine, 5-carboxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl- pseudouridine, uridine, 5-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1- methyl-pseudouridine, uridine, 5-trifluoromethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-hydroxymethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-bromo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-iodo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-methoxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-ethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-phenyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-ethnyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, N4-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-fluoro-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, N4-acetyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, pseudoisocytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-formyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5-aminoallyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain 1-methyl-pseudouridine, uridine, 5- carboxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the disclosure contain the uracil of one of the nucleosides of Table 2 and uracil as the only uracils. In other embodiments, the polynucleotides of the disclosure contain a uridine of Table 2 and uridine as the only uridines. Table 2. Exemplary uracil-containing nucleosides

In some embodiments, the polynucleotides of the disclosure contain the cytosine of one of the nucleosides of Table 3 and cytosine as the only cytosines. In other embodiments, the polynucleotides of the disclosure contain a cytidine of Table 3 and cytidine as the only cytidines. Table 3. Exemplary cytosine containing nucleosides

Alterations on the internucleoside linkage The alternative nucleotides, which may be incorporated into a polynucleotide molecule, can be altered on the internucleoside linkage (e.g., phosphate backbone). Herein, in the context of the polynucleotide backbone, the phrases “phosphate” and “phosphodiester” are used interchangeably. Backbone phosphate groups can be altered by replacing one or more of the oxygen atoms with a different substituent. The alternative nucleosides and nucleotides can include the wholesale replacement of an unaltered phosphate moiety with another internucleoside linkage as described herein. Examples of alternative phosphate groups include, but are not limited to, phosphorothioate, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, phosphorodiamidates, alkyl or aryl phosphonates, and phosphotriesters. Phosphorodithioates have both non-linking oxygens replaced by sulfur. The phosphate linker can also be altered by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), and carbon (bridged methylene-phosphonates). The alternative nucleosides and nucleotides can include the replacement of one or more of the non-bridging oxygens with a borane moiety (BH₃), sulfur (thio), methyl, ethyl and/or methoxy. As a non-limiting example, two non-bridging oxygens at the same position (e.g., the alpha (α), beta (β) or gamma (γ) position) can be replaced with a sulfur (thio) and a methoxy. The replacement of one or more of the oxygen atoms at the α position of the phosphate moiety (e.g., α-thio phosphate) is provided to confer stability (such as against exonucleases and endonucleases) to RNA and DNA through the unnatural phosphorothioate backbone linkages. Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment. While not wishing to be bound by theory, phosphorothioate linked polynucleotide molecules are expected to also reduce the innate immune response through weaker binding/activation of cellular innate immune molecules. In specific embodiments, an alternative nucleoside includes an alpha-thio- nucleoside (e.g., 5′-O-(1-thiophosphate)-adenosine, 5′-O-(1-thiophosphate)-cytidine (α-thio-cytidine), 5′-O-(1-thiophosphate)-guanosine, 5′-O-(1-thiophosphate)-uridine, or 5′-O-(1-thiophosphate)-pseudouridine). Other internucleoside linkages that may be employed according to the present disclosure, including internucleoside linkages which do not contain a phosphorous atom, are described herein below. Combinations of alternative sugars, nucleobases, and internucleoside linkages The polynucleotides of the disclosure can include a combination of alterations to the sugar, the nucleobase, and/or the internucleoside linkage. These combinations can include any one or more alterations described herein. Synthesis of polynucleotides The polynucleotide molecules for use in accordance with the disclosure may be prepared according to any useful technique, as described herein. The alternative nucleosides and nucleotides used in the synthesis of polynucleotide molecules disclosed herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are provided, a skilled artisan would be able to optimize and develop additional process conditions. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography). Preparation of polynucleotide molecules of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety. The reactions of the processes described herein can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out (i.e., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. Resolution of racemic mixtures of alternative polynucleotides or nucleic acids (e.g., polynucleotides or mRNA molecules) can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a “chiral resolving acid” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Alternative nucleosides and nucleotides (e.g., building block molecules) can be prepared according to the synthetic methods described in Ogata et al., J. Org. Chem.74:2585-2588 (2009); Purmal et al., Nucl. Acids Res.22(1): 72-78, (1994); Fukuhara et al., Biochemistry, 1(4): 563-568 (1962); and Xu et al., Tetrahedron, 48(9): 1729-1740 (1992), each of which are incorporated by reference in their entirety. If the polynucleotide includes one or more alternative nucleosides or nucleotides, the polynucleotides of the disclosure may or may not be uniformly altered along the entire length of the molecule. For example, one or more or all types of nucleotide (e.g., purine or pyrimidine, or any one or more or all of A, G, U, C) may or may not be uniformly altered in a polynucleotide of the disclosure, or in a given predetermined sequence region thereof. In some embodiments, all nucleotides X in a polynucleotide of the disclosure (or in a given sequence region thereof) are altered, wherein X may any one of nucleotides A, G, U, C, or any one of the combinations A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C or A+G+C. Different sugar alterations, nucleotide alterations, and/or internucleoside linkages (e.g., backbone structures) may exist at various positions in the polynucleotide. One of ordinary skill in the art will appreciate that the nucleotide analogs or other alteration(s) may be located at any position(s) of a polynucleotide such that the function of the polynucleotide is not substantially decreased. An alteration may also be a 5′ or 3′ terminal alteration. The polynucleotide may contain from 1% to 100% alternative nucleosides, nucleotides, or internucleoside linkages (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e. any one or more of A, G, U or C) or any intervening percentage (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 80% to 100%, from 90% to 95%, from 90% to 100%, and from 95% to 100. In some embodiments, the remaining percentage is accounted for by the presence of A, G, U, or C. When referring to percentage incorporation by an alternative nucleoside, nucleotide, or internucleoside linkage, in some embodiments the remaining percentage necessary to total 100% is accounted for by the corresponding natural nucleoside, nucleotide, or internucleoside linkage. In other embodiments, the remaining percentage necessary to total 100% is accounted for by a second alternative nucleoside, nucleotide, or internucleoside linkage. Messenger RNA The present disclosure provides compositions including one or more mRNAs, where each mRNA encodes a polypeptide. Exemplary mRNAs of the disclosure each include (i) a 5’-cap structure; (ii) a 5’-UTR; (iii) an open reading frame encoding the polypeptide; (iv) a 3’-untranslated region (3’-UTR); and (v) a poly-A region. In some embodiments, the mRNA includes from about 30 to about 3,000 (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, or from 2,500 to 3,000) nucleotides. More specifically, provided herein are nucleic acids that encode VHH domains and anti-CD28 binding proteins of the disclosure. Any of the proteins disclosed herein may be encoded by an open reading frame (ORF) of an mRNA. In some embodiments, the ORF of the mRNA comprises a nucleic acid sequence of: ATGGAGACCCCTGCCCAGCTGCTGTTCCTGCTGCTGCTGTGGCTGCCCGACACCA CCGGCGAGGTGCAGCTGGTGGAGTCAGGCGGCGGGCTGGTTCAGCCCGGCGGC TCTCTGCGACTGAGCTGCGCTGCCAGCGGAAGCGTGTTCAGCGGCAACGTGATG GGCTGGTACCGGCAGGCCCCTGGCAAGCAGCGGGAGCTGGTGGCAGCCATCAC CAGCGGCGGAAGCGCCACCTACGAGGACAGCGTGAAGGGCCGGTTTACCATCAG CCGGGACAACAGCAAGAACACCGTGTATCTGCAGATGAACAGCCTGAGAGCCGAG GACACCGCCATCTACTACTGCGCCGCCGACAACTGGGGCATCGTGCGGTGGAGA GCCCCAGACTACTGGGGACAGGGCACCCTGGTGACCGTGAGCTCAGGCGGTGGC GGATCTGGCGGAGGCGGCTCTGGAGGTGGAGGCAGCGCCCACAAGAGCGAGGT GGCCCACAGATTCAAGGACCTGGGCGAGGAGAACTTCAAGGCCCTGGTGCTGAT CGCCTTCGCCCAGTACCTGCAGCAGTGCCCTTTCGAGGACCACGTGAAGCTGGTG AACGAGGTGACCGAGTTCGCCAAGACCTGCGTGGCCGACGAGAGCGCCGAGAAC TGCGACAAGAGCCTGCACACCCTGTTCGGCGACAAGCTGTGCACCGTGGCCACC CTGAGAGAAACTTACGGCGAGATGGCCGACTGCTGCGCCAAGCAGGAGCCAGAG CGGAACGAGTGCTTCCTCCAGCACAAGGACGACAACCCTAACCTGCCTAGACTGG TAAGGCCTGAGGTGGACGTGATGTGTACCGCCTTCCACGACAACGAGGAGACATT CCTGAAGAAGTACCTGTACGAGATCGCCAGAAGACACCCTTACTTCTACGCCCCT GAGTTGCTGTTCTTCGCGAAGAGATACAAGGCCGCCTTCACCGAGTGCTGCCAGG CCGCCGATAAGGCCGCGTGCCTGCTGCCTAAGCTGGACGAGCTGAGAGACGAGG GCAAGGCATCCAGCGCTAAGCAGAGACTGAAGTGCGCCAGCCTGCAGAAGTTCG GAGAGAGAGCTTTCAAGGCGTGGGCAGTGGCTAGATTGAGCCAAAGATTCCCTAA GGCAGAATTCGCTGAGGTGAGCAAGCTCGTGACTGACCTGACCAAGGTGCATACA GAGTGCTGTCACGGCGACCTGCTGGAGTGCGCCGACGACAGAGCCGACCTGGCC AAGTACATCTGCGAGAACCAGGACAGCATCAGCAGCAAGCTGAAGGAGTGTTGTG AGAAGCCTCTATTGGAGAAGAGTCACTGCATTGCCGAGGTGGAGAACGACGAGAT GCCTGCGGATCTGCCAAGCTTGGCGGCCGACTTCGTGGAGAGCAAGGACGTGTG CAAGAACTACGCCGAGGCCAAGGACGTTTTCCTGGGCATGTTCCTCTACGAGTAC GCACGCAGACATCCAGACTACAGCGTGGTGCTGCTGCTGAGACTGGCTAAGACAT ACGAAACTACCCTGGAGAAGTGCTGCGCAGCGGCGGACCCTCACGAGTGTTACG CCAAGGTGTTCGACGAGTTCAAGCCTCTGGTGGAGGAGCCTCAGAACCTGATCAA GCAGAACTGTGAGCTGTTCGAGCAGCTCGGCGAGTACAAGTTCCAGAACGCCCTG TTGGTCCGCTACACCAAGAAGGTGCCTCAAGTAAGTACCCCTACCCTGGTAGAGG TTAGTAGAAACCTGGGCAAGGTGGGCAGCAAGTGCTGTAAGCACCCAGAAGCTAA GAGGATGCCTTGCGCCGAGGACTACCTGTCCGTTGTGCTGAACCAGCTGTGCGTG CTGCACGAGAAGACCCCTGTGAGCGACAGAGTGACAAAGTGTTGCACCGAGAGCT TAGTGAATAGAAGACCTTGCTTCAGCGCCCTGGAAGTTGACGAAACTTACGTGCCT AAGGAGTTCAACGCCGAGACTTTCACATTCCACGCCGACATTTGCACTCTGAGCGA GAAGGAGAGACAGATCAAGAAGCAGACCGCCCTCGTAGAGTTGGTCAAGCACAAG CCGAAGGCAACCAAGGAACAGCTTAAGGCCGTGATGGACGACTTCGCAGCCTTCG TCGAGAAGTGTTGTAAGGCCGACGACAAGGAGACTTGCTTCGCAGAGGAAGGCAA GAAGTTGGTAGCCGCCTCTCAGGCTGCCTTGGGACTC (SEQ ID NO: 77). In some embodiments, the mRNA may comprise, in the 5’-to-3’ direction: (a) a 5’ untranslated region (UTR); (b) an open reading frame encoding the antibody, wherein the open reading frame optionally consists of nucleosides selected from the group consisting of (i) uridine or a modified uridine, (ii) cytidine or a modified cytidine, (iii) adenosine or a modified adenosine, and (iv) guanosine or a modified guanosine; and (c) a 3’ UTR. In some embodiments, the open reading frame has a nucleic acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the nucleic acid sequence of SEQ ID NO: 77. For example, in some embodiments, the open reading frame is at least 90% identical to the nucleic acid sequence of SEQ ID NO: 77. In some embodiments, the open reading frame is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 77. In some embodiments, the open reading frame has the nucleic acid sequence of SEQ ID NO: 77. Similar such open reading frames can be designed from the protein sequences disclosed herein or with alternate VHH binding domains or FC domains known in the art using the genetic code and the codon optimization strategies known to one of ordinary skill in the art. In one embodiment, the mRNA may comprise, in the 5’-to-3’ direction: (a) a 5’ untranslated region (UTR) having SEQ ID NO: 78; (b) an open reading frame having SEQ ID NO: 77; and (c) a 3’ UTR having SEQ ID NO: 79. In one embodiment, the polynucleotide (e.g., mRNA) comprising a 5’ untranslated region (UTR) having SEQ ID NO: 78, an open reading frame having SEQ ID NO: 77, and a 3’ UTR having SEQ ID NO: 79, encodes an anti-CD28 polypeptide having SEQ ID NO: 81. In some embodiments, the sequence encoding the polypeptide also comprises a leader sequence or signal peptide that may be cleaved off of the mature antibody during post-translational processing, e.g. SEQ ID NO: 75. In some embodiments, the polypeptide has a sequence of SEQ ID NO: 158. In some embodiments, the polypeptide has a sequence of SEQ ID NO: 81. In some embodiments, the polynucleotide comprising a 5’ untranslated region (UTR) having SEQ ID NO: 78, an open reading frame having SEQ ID NO: 77, and a 3’ UTR having SEQ ID NO: 79 is formulated as an LNP. In one embodiment, the LNP is LNP-1B. mRNA and amino acid sequences encoding an embodiment of an anti-CD28 binding protein of the disclosure are shown in Table 4 below: Table 4 - Modular Construct Sequences for anti-CD28 binding protein

Untranslated Regions (UTRs) Untranslated regions (UTRs) are nucleic acid sections of a polynucleotide before a start codon (5′ UTR) and after a stop codon (3′ UTR) that are not translated. In some embodiments, a polynucleotide (e.g., a ribonucleic acid (RNA), e.g., a messenger RNA (mRNA)) of the present disclosure comprising an open reading frame (ORF) encoding an anti-CD28 polypeptide further comprises a UTR (e.g., a 5′ UTR or functional fragment thereof, a 3′ UTR or functional fragment thereof, or a combination thereof). A UTR (e.g., 5′ UTR or 3′ UTR) can be homologous or heterologous to the coding region in a polynucleotide. In some embodiments, the UTR is homologous to the ORF encoding the anti-CD28 polypeptide. In some embodiments, the UTR is heterologous to the ORF encoding the anti-CD28 polypeptide. In some embodiments, the polynucleotide comprises two or more 5′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the polynucleotide comprises two or more 3′ UTRs or functional fragments thereof, each of which has the same or different nucleotide sequences. In some embodiments, the 5′ UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof is sequence optimized. In some embodiments, the 5′UTR or functional fragment thereof, 3′ UTR or functional fragment thereof, or any combination thereof comprises at least one chemically modified nucleobase, e.g., N1-methylpseudouracil or 5-methoxyuracil. UTRs can have features that provide a regulatory role, e.g., increased or decreased stability, localization and/or translation efficiency. A polynucleotide comprising a UTR can be administered to a cell, tissue, or organism, and one or more regulatory features can be measured using routine methods. In some embodiments, a functional fragment of a 5′ UTR or 3′ UTR comprises one or more regulatory features of a full length 5′ or 3′ UTR, respectively. Natural 5′UTRs bear features that play roles in translation initiation. They harbor signatures like Kozak sequences that are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG (SEQ ID NO: 80), where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’.5′ UTRs also have been known to form secondary structures that are involved in elongation factor binding. By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of a polynucleotide. For example, introduction of 5′ UTR of liver-expressed mRNA, such as albumin, serum amyloid A, Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, can enhance expression of polynucleotides in hepatic cell lines or liver. Likewise, use of 5′UTR from other tissue-specific mRNA to improve expression in that tissue is possible for muscle (e.g., MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (e.g., Tie-1, CD36), for myeloid cells (e.g., C/EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (e.g., CD45, CD18), for adipose tissue (e.g., CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (e.g., SP-A/B/C/D). In some embodiments, UTRs are selected from a family of transcripts whose proteins share a common function, structure, feature or property. For example, an encoded polypeptide can belong to a family of proteins (i.e., that share at least one function, structure, feature, localization, origin, or expression pattern), which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of the genes or mRNA can be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. In some embodiments, the 5′ UTR and the 3′ UTR can be heterologous. In some embodiments, the 5′ UTR can be derived from a different species than the 3′ UTR. In some embodiments, the 3′ UTR can be derived from a different species than the 5′ UTR. Co-owned International Patent Application No. PCT/US2014/021522 (Publ. No. WO/2014/164253, incorporated herein by reference in its entirety) provides a listing of exemplary UTRs that can be utilized in the polynucleotide of the present disclosure as flanking regions to an ORF. Further exemplary UTRs are listed in Tables 4 and 5, below. Additional exemplary UTRs of the application include, but are not limited to, one or more 5′UTR and/or 3′UTR derived from the nucleic acid sequence of: a globin, such as an α- or β-globin (e.g., a Xenopus, mouse, rabbit, or human globin); a strong Kozak translational initiation signal; a CYBA (e.g., human cytochrome b-245 α polypeptide); an albumin (e.g., human albumin7); a HSD17B4 (hydroxysteroid (17-β) dehydrogenase); a virus (e.g., a tobacco etch virus (TEV), a Venezuelan equine encephalitis virus (VEEV), a Dengue virus, a cytomegalovirus (CMV) (e.g., CMV immediate early 1 (IE1)), a hepatitis virus (e.g., hepatitis B virus), a sindbis virus, or a PAV barley yellow dwarf virus); a heat shock protein (e.g., hsp70); a translation initiation factor (e.g., elF4G); a glucose transporter (e.g., hGLUT1 (human glucose transporter 1)); an actin (e.g., human α or β actin); a GAPDH; a tubulin; a histone; a citric acid cycle enzyme; a topoisomerase (e.g., a 5′UTR of a TOP gene lacking the 5′ TOP motif (the oligopyrimidine tract)); a ribosomal protein Large 32 (L32); a ribosomal protein (e.g., human or mouse ribosomal protein, such as, for example, rps9); an ATP synthase (e.g., ATP5A1 or the β subunit of mitochondrial H⁺-ATP synthase); a growth hormone (e.g., bovine (bGH) or human (hGH)); an elongation factor (e.g., elongation factor 1 α1 (EEF1A1)); a manganese superoxide dismutase (MnSOD); a myocyte enhancer factor 2A (MEF2A); a β-F1-ATPase, a creatine kinase, a myoglobin, a granulocyte-colony stimulating factor (G-CSF); a collagen (e.g., collagen type I, alpha 2 (Col1A2), collagen type I, alpha 1 (Col1A1), collagen type VI, alpha 2 (Col6A2), collagen type VI, alpha 1 (Col6A1)); a ribophorin (e.g., ribophorin I (RPNI)); a low density lipoprotein receptor- related protein (e.g., LRP1); a cardiotrophin-like cytokine factor (e.g., Nnt1); calreticulin (Calr); a procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (Plod1); and a nucleobindin (e.g., Nucb1). In some embodiments, the 5′ UTR is selected from the group consisting of a β- globin 5′ UTR; a 5′UTR containing a strong Kozak translational initiation signal; a cytochrome b-245 α polypeptide (CYBA) 5′ UTR; a hydroxysteroid (17-β) dehydrogenase (HSD17B4) 5′ UTR; a Tobacco etch virus (TEV) 5′ UTR; a Venezuelen equine encephalitis virus (TEEV) 5′ UTR; a 5′ proximal open reading frame of rubella virus (RV) RNA encoding nonstructural proteins; a Dengue virus (DEN) 5′ UTR; a heat shock protein 70 (Hsp70) 5′ UTR; a eIF4G 5′ UTR; a GLUT15′ UTR; functional fragments thereof and any combination thereof. In some embodiment, the mRNA comprises a 5’-UTR comprising a nucleic acid sequence of AGGAAATCGCAAAATTTGCTCTTCGCGTTAGATTTCTTTTAGTTTTCTCGCAACTAG CAAGCTTTTTGTTCTCGCC (SEQ ID NO: 78). In some embodiment, the mRNA comprises a 3’-UTR comprising a nucleic acid sequence of TAAGCCCCTCCGGGGGCCTCGGTGGCCTAGCTTCTTGCCCCTTGGGCCTCCCCC CAGCCCCTCCTCCCCTTCCTGCACCCGTACCCCCGTGGTCTTTGAATAAAGTCTGA GTGGGCGGC (SEQ ID NO: 79). In some embodiments, the 3′ UTR is selected from the group consisting of a β- globin 3′ UTR; a CYBA 3′ UTR; an albumin 3′ UTR; a growth hormone (GH) 3′ UTR; a VEEV 3′ UTR; a hepatitis B virus (HBV) 3′ UTR; α-globin 3′UTR; a DEN 3′ UTR; a PAV barley yellow dwarf virus (BYDV-PAV) 3′ UTR; an elongation factor 1 α1 (EEF1A1) 3′ UTR; a manganese superoxide dismutase (MnSOD) 3′ UTR; a β subunit of mitochondrial H(+)-ATP synthase (β-mRNA) 3′ UTR; a GLUT13′ UTR; a MEF2A 3′ UTR; a β-F1-ATPase 3′ UTR; functional fragments thereof, and combinations thereof. Wild-type UTRs derived from any gene or mRNA can be incorporated into the polynucleotides of the present disclosure. In some embodiments, a UTR can be altered relative to a wild type or native UTR to produce a variant UTR, e.g., by changing the orientation or location of the UTR relative to the ORF; or by inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. In some embodiments, variants of 5′ or 3′ UTRs can be utilized, for example, mutants of wild type UTRs, or variants wherein one or more nucleotides are added to or removed from a terminus of the UTR. Additionally, one or more synthetic UTRs can be used in combination with one or more non-synthetic UTRs. See, e.g., Mandal and Rossi, Nat. Protoc.20138(3):568-82, the contents of which are incorporated herein by reference in their entirety. UTRs or portions thereof can be placed in the same orientation as in the transcript from which they were selected or can be altered in orientation or location. Hence, a 5′ and/or 3′ UTR can be inverted, shortened, lengthened, or combined with one or more other 5′ UTRs or 3′ UTRs. In some embodiments, the polynucleotide comprises multiple UTRs, e.g., a double, a triple or a quadruple 5′ UTR or 3′ UTR. For example, a double UTR comprises two copies of the same UTR either in series or substantially in series. For example, a double beta-globin 3′UTR can be used (see US2010/0129877, the contents of which are incorporated herein by reference in its entirety). The polynucleotides of the present disclosure can comprise combinations of features. For example, the ORF can be flanked by a 5′UTR that comprises a strong Kozak translational initiation signal and/or a 3′UTR comprising an oligo(dT) sequence for templated addition of a poly-A tail. A 5′UTR can comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different UTRs (see, e.g., US2010/0293625, herein incorporated by reference in its entirety). Other non-UTR sequences can be used as regions or subregions within the polynucleotides of the present disclosure. For example, introns or portions of intron sequences can be incorporated into the polynucleotides of the present disclosure. Incorporation of intronic sequences can increase protein production as well as polynucleotide expression levels. In some embodiments, the polynucleotide of the present disclosure comprises an internal ribosome entry site (IRES) instead of or in addition to a UTR (see, e.g., Yakubov et al., Biochem. Biophys. Res. Commun.2010 394(1):189-193, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the polynucleotide comprises an IRES instead of a 5′ UTR sequence. In some embodiments, the polynucleotide comprises an ORF and a viral capsid sequence. In some embodiments, the polynucleotide comprises a synthetic 5′ UTR in combination with a non-synthetic 3′ UTR. In some embodiments, the UTR can also include at least one translation enhancer polynucleotide, translation enhancer element, or translational enhancer elements (collectively, "TEE," which refers to nucleic acid sequences that increase the amount of polypeptide or protein produced from a polynucleotide. As a non-limiting example, the TEE can be located between the transcription promoter and the start codon. In some embodiments, the 5′ UTR comprises a TEE. In one aspect, a TEE is a conserved element in a UTR that can promote translational activity of a nucleic acid such as, but not limited to, cap-dependent or cap- independent translation. 5’ UTR Sequences In some embodiment, the mRNA comprises a 5’-UTR comprising a nucleic acid sequence of AGGAAATCGCAAAATTTGCTCTTCGCGTTAGATTTCTTTTAGTTTTCTCGCAACTAG CAAGCTTTTTGTTCTCGCC (SEQ ID NO: 78). In some embodiments, the polynucleotide having a 5′ UTR sequence provided in Table 5 or a variant or fragment thereof, has an increase in the half-life of the polynucleotide, e.g., about 1.5-20-fold increase in half-life of the polynucleotide. In some embodiments, the increase in half-life is about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-fold, or more. In some embodiments, the increase in half life is about 1.5-fold or more. In some embodiments, the increase in half life is about 2-fold or more. In some embodiments, the increase in half life is about 3- fold or more. In some embodiments, the increase in half life is about 4-fold or more. In some embodiments, the increase in half life is about 5-fold or more. In some embodiments, the polynucleotide having a 5′ UTR sequence provided in Table 5 or a variant or fragment thereof, results in an increased level and/or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In some embodiments, the 5′UTR results in about 1.5-20-fold increase in level and/or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In some embodiments, the increase in level and/or activity is about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-fold, or more. In some embodiments, the increase in level and/or activity is about 1.5-fold or more. In some embodiments, the increase in level and/or activity is about 2-fold or more. In some embodiments, the increase in level and/or activity is about 3-fold or more. In some embodiments, the increase in level and/or activity is about 4-fold or more. In some embodiments, the increase in level and/or activity is about 5-fold or more. In some embodiments, the increase is compared to an otherwise similar polynucleotide which does not have a 5′ UTR, has a different 5′ UTR, or does not have a 5′ UTR described in Table 5 or a variant or fragment thereof. In some embodiments, the increase in half-life of the polynucleotide is measured according to an assay that measures the half-life of a polynucleotide. In some embodiments, the increase in level and/or activity, e.g., output, of the polypeptide encoded by the polynucleotide is measured according to an assay that measures the level and/or activity of a polypeptide. In some embodiments, the 5′ UTR comprises a sequence provided in Table 5 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 5′ UTR sequence provided in Table 5, or a variant or a fragment thereof. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, or SEQ ID NO: 110. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 82. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 83. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 84. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 85. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 86. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 87. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 88. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 89. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 90. In some embodiments, the 5′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 110. In some embodiments, the 5′ UTR comprises the sequence of SEQ ID NO: 82. In some embodiments, the 5′ UTR consists of the sequence of SEQ ID NO: 82. In some embodiments, the 5′ UTR comprises the sequence of SEQ ID NO: 87. In some embodiments, the 5′ UTR consists of the sequence of SEQ ID NO: 87. In some embodiments, the 5′ UTR comprises the sequence of SEQ ID NO: 88. In some embodiments, the 5′ UTR consists of the sequence of SEQ ID NO: 88. In some embodiments, the 5′ UTR comprises the sequence of SEQ ID NO: 110. In some embodiments, the 5′ UTR consists of the sequence of SEQ ID NO: 110. In some embodiments, a 5′ UTR sequence provided in Table 5 has a first nucleotide (not shown) which is an A. In some embodiments, a 5′ UTR sequence provided in Table 5 has a first nucleotide (not shown) which is a G. Table 5 – 5’ UTR Sequences

In some embodiments, the variant of SEQ ID NO: 82 comprises a nucleic acid sequence of Formula A: G G A A A U C G C A A A A (N₂)_X (N₃)_X C U (N₄)_X (N₅)_X C G C G U U A G A U U U C U U U U A G U U U U C U N₆ N₇ C A A C U A G C A A G C U U U U U G U U C U C G C C (N₈ C C)x (SEQ ID NO: 491), wherein: (N₂)_x is a uracil and x is an integer from 0 to 5, e.g., wherein x =3 or 4; (N₃)_x is a guanine and x is an integer from 0 to 1; (N₄)_x is a cytosine and x is an integer from 0 to 1; (N₅)_x is a uracil and x is an integer from 0 to 5, e.g., wherein x =2 or 3; N₆ is a uracil or cytosine; N₇ is a uracil or guanine; and N₈ is adenine or guanine and x is an integer from 0 to 1. In some embodiments (N₂)_x is a uracil and x is 0. In some embodiments (N₂)_x is a uracil and x is 1. In some embodiments (N₂)_x is a uracil and x is 2. In some embodiments (N₂)_x is a uracil and x is 3. In some embodiments, (N₂)_x is a uracil and x is 4. In some embodiments (N₂)_x is a uracil and x is 5. In some embodiments, (N₃)_x is a guanine and x is 0. In some embodiments, (N₃)_x is a guanine and x is 1. In some embodiments, (N₄)_x is a cytosine and x is 0. In some embodiments, (N₄)_x is a cytosine and x is 1. In some embodiments, (N₅)_x is a uracil and x is 0. In some embodiments, (N₅)_x is a uracil and x is 1. In some embodiments, (N₅)_x is a uracil and x is 2. In some embodiments, (N₅)_x is a uracil and x is 3. In some embodiments, (N₅)_x is a uracil and x is 4. In some embodiments (N₅)_x is a uracil and x is 5. In some embodiments, N6 is a uracil. In some embodiments, N6 is a cytosine. In some embodiments, N7 is a uracil. In some embodiments, N7 is a guanine. In some embodiments, N8 is an adenine and x is 0. In some embodiments, N8 is an adenine and x is 1. In some embodiments, N8 is a guanine and x is 0. In some embodiments, N8 is a guanine and x is 1. In some embodiments, the 5′ UTR comprises a variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant comprises a sequence with at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 50% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 60% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 70% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 80% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 90% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 95% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 96% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 97% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 98% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a sequence with at least 99% identity to SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 5%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 10%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 20%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 30%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 40%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 50%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 60%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 70%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises a uridine content of at least 80%. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises at least 2, 3, 4, 5, 6 or 7 consecutive uridines (e.g., a polyuridine tract). In some embodiments, the polyuridine tract in the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises at least 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, or 3-5 consecutive uridines. In some embodiments, the polyuridine tract in the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 4 consecutive uridines. In some embodiments, the polyuridine tract in the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 5 consecutive uridines. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 polyuridine tracts. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 3 polyuridine tracts. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 4 polyuridine tracts. In some embodiments, the variant of SEQ ID NO: 82, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 110 comprises 5 polyuridine tracts. In some embodiments, one or more of the polyuridine tracts are adjacent to a different polyuridine tract. In some embodiments, each of, e.g., all, the polyuridine tracts are adjacent to each other, e.g., all of the polyuridine tracts are contiguous. In some embodiments, one or more of the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides. In some embodiments, each of, e.g., all of, the polyuridine tracts are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides. In some embodiments, a first polyuridine tract and a second polyuridine tract are adjacent to each other. In some embodiments, a subsequent, e.g., third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth, polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides from the first polyuridine tract, the second polyuridine tract, or any one of the subsequent polyuridine tracts. In some embodiments, a first polyuridine tract is separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2, 13, 14, 15, 16, 17, 18.19, 20, 30, 40, 50 or 60 nucleotides from a subsequent polyuridine tract, e.g., a second, third, fourth, fifth, sixth or seventh, eighth, ninth, or tenth polyuridine tract. In some embodiments, one or more of the subsequent polyuridine tracts are adjacent to a different polyuridine tract. In some embodiments, the 5′ UTR comprises a Kozak sequence, e.g., a GCCRCC nucleotide sequence (SEQ ID NO:111) wherein R is an adenine or guanine. In some embodiments, the Kozak sequence is disposed at the 3′ end of the 5′UTR sequence. In an aspect, the polynucleotide (e.g., mRNA) comprising an open reading frame (e.g., SEQ ID NO: 77) encoding an anti-CD28 polypeptide (e.g., SEQ ID NO: 81) and comprising a 5′ UTR sequence disclosed herein is formulated as an LNP. In some embodiments, the LNP composition comprises: (i) an ionizable lipid, e.g., an amino lipid; (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG-lipid. In another aspect, the LNP compositions of the disclosure are used in a method of treating argininosuccinic aciduria in a subject. In another aspect, an LNP composition comprising a polynucleotide disclosed herein encoding an anti-CD28 polypeptide, e.g., as described herein, can be administered with an additional agent, e.g., as described herein. 3′ UTR sequences 3′UTR sequences have been shown to influence translation, half-life, and subcellular localization of mRNAs (Mayr C., Cold Spring Harb. Persp. Biol.2019 Oct 1;11(10):a034728). Disclosed herein, inter alia, is a polynucleotide, e.g., mRNA, comprising an open reading frame (e.g., of SEQ ID NO: 77) encoding a CD28 antibody (e.g., of SEQ ID NO: 80), which polynucleotide has a 3′ UTR that confers an increased half-life, increased expression and/or increased activity of the polypeptide encoded by said polynucleotide, or of the polynucleotide itself., a polynucleotide disclosed herein comprises: (a) a 5′- UTR (e.g., as provided in Table 5 or a variant or fragment thereof ); (b) a coding region comprising a stop element (e.g., as described herein); and (c) a 3′-UTR (e.g., as provided in Table 6 or a variant or fragment thereof), and LNP compositions comprising the same. In some embodiment, the mRNA comprises a 3’-UTR comprising a nucleic acid sequence of TAAGCCCCTCCGGGGGCCTCGGTGGCCTAGCTTCTTGCCCCTTGGGCCTCCCCC CAGCCCCTCCTCCCCTTCCTGCACCCGTACCCCCGTGGTCTTTGAATAAAGTCTGA GTGGGCGGC (SEQ ID NO: 79). In some embodiments, the polynucleotide having a 3′ UTR sequence provided in Table 6 or a variant or fragment thereof, results in an increased half-life of the polynucleotide, e.g., about 1.5-10-fold increase in half-life of the polynucleotide. In some embodiments, the increase in half-life is about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-fold, or more. In some embodiments, the increase in half-life is about 1.5-fold or more. In some embodiments, the increase in half-life is about 2-fold or more. In some embodiments, the increase in half-life is about 3-fold or more. In some embodiments, the increase in half-life is about 4-fold or more. In some embodiments, the increase in half-life is about 5-fold or more. In some embodiments, the increase in half-life is about 6-fold or more. In some embodiments, the increase in half-life is about 7-fold or more. In some embodiments, the increase in half-life is about 8-fold. In some embodiments, the increase in half-life is about 9-fold or more. In some embodiments, the increase in half- life is about 10-fold or more. In some embodiments, the polynucleotide having a 3′ UTR sequence provided in Table 6 or a variant or fragment thereof, results in a polynucleotide with a mean half-life score of greater than 10. In some embodiments, the polynucleotide having a 3′ UTR sequence provided in Table 6 or a variant or fragment thereof, results in an increased level and/or activity, e.g., output, of the polypeptide encoded by the polynucleotide. In some embodiments, the increase is compared to an otherwise similar polynucleotide which does not have a 3′ UTR, has a different 3′ UTR, or does not have a 3′ UTR of Table 6 or a variant or fragment thereof. In some embodiments, the polynucleotide comprises a 3′ UTR sequence provided in Table 6 or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to a 3′ UTR sequence provided in Table 6, or a fragment thereof. In some embodiments, the 3′ UTR comprises a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 137, SEQ ID NO: 138, and SEQ ID NO: 139. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 112, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 112. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 113, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 113. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 114, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 114. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 115, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 115. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 116, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO :116. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 117, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 117. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 118, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 118. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 119, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 119. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 120, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 120. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 121, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 121. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 122, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 122. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 123, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 123. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 124, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 124. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 125, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 125. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 126, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 126. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 127, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 127. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 137, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 137. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 138, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 138. In some embodiments, the 3′ UTR comprises the sequence of SEQ ID NO: 139, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 139. Table 6 – 3’ UTR Sequences

mRNA: Coding region Provided are nucleic acids that encode antibodies of the disclosure and fragments thereof. As recognized by those skilled in the art, protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of this present disclosure. For example, provided herein is any protein fragment of a reference protein (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or greater than 100 amino acids in length. In another example, any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids which are about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% identical to any of the sequences described herein can be utilized in accordance with the present disclosure. In certain embodiments, a protein sequence to be utilized in accordance with the present disclosure includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein. mRNA: Stem-loops In some embodiments, the nucleic acids of the present disclosure (e.g., the mRNA of the present disclosure) may include a stem-loop such as, but not limited to, a histone stem-loop. The stem-loop may be a nucleotide sequence that is about 25 or about 26 nucleotides in length such as, but not limited to, SEQ ID NOs: 7-17 as described in International Patent Publication No. WO2013/103659, incorporated herein by reference in its entirety. The histone stem-loop may be located 3’ relative to the coding region (e.g., at the 3’ terminus of the coding region). As a non-limiting example, the stem-loop may be located at the 3’ end of a nucleic acid described herein. In some embodiments, the stem-loop may be located in the second terminal region. As a non-limiting example, the stem-loop may be located within an untranslated region (e.g., 3’-UTR) in the second terminal region. In some embodiments, the nucleic acid such as, but not limited to mRNA, which includes the histone stem-loop may be stabilized by the addition of at least one chain terminating nucleoside. Not wishing to be bound by theory, the addition of at least one chain terminating nucleoside may slow the degradation of a nucleic acid and thus can increase the half-life of the nucleic acid. In some embodiments, the chain terminating nucleoside may be, but is not limited to, those described in International Patent Publication No. WO2013/103659, incorporated herein by reference in its entirety. In some embodiments, the chain terminating nucleosides which may be used with the present disclosure includes, but is not limited to, 3'-deoxyadenosine (cordycepin), 3'-deoxyuridine, 3'-deoxycytosine, 3'- deoxyguanosine, 3'-deoxythymine, 2',3'-dideoxynucleosides, such as 2',3'- dideoxyadenosine, 2',3'-dideoxyuridine, 2',3'-dideoxycytosine, 2',3'- dideoxyguanosine, 2',3'-dideoxythymine, a 2'-deoxynucleoside, or a -O- methylnucleoside. In some embodiments, the nucleic acid such as, but not limited to mRNA, which includes the histone stem-loop may be stabilized by an alteration to the 3’region of the nucleic acid that can prevent and/or inhibit the addition of oligo(U) (see e.g., International Patent Publication No. WO2013/103659, incorporated herein by reference in its entirety). In yet another embodiment, the nucleic acid such as, but not limited to, mRNA, which includes the histone stem-loop may be stabilized by the addition of an oligonucleotide that terminates in a 3’-deoxynucleoside, 2’,3’-dideoxynucleoside 3'-O- methylnucleosides, 3'-O-ethylnucleosides, 3'-arabinosides, and other alternative nucleosides known in the art and/or described herein. In some embodiments, the nucleic acids of the present disclosure may include a histone stem-loop, a poly-A tail sequence, and/or a 5’-cap structure. The histone stem- loop may be before and/or after the poly-A tail sequence. The nucleic acids including the histone stem-loop and a poly-A tail sequence may include a chain terminating nucleoside described herein. In some embodiments, the nucleic acids of the present disclosure may include a histone stem-loop and a 5’-cap structure. The 5’-cap structure may include, but is not limited to, those described herein and/or known in the art. In some embodiments, the nucleic acids described herein may include at least one histone stem-loop and a poly-A sequence or polyadenylation signal. Non-limiting examples of nucleic acid sequences encoding for at least one histone stem-loop and a poly-A sequence or a polyadenylation signal are described in International Patent Publication Nos. WO2013/120497, WO2013/120629, WO2013/120500, WO2013/120627, WO2013/120498, WO2013/120626, WO2013/120499 and WO2013/120628, the contents of each of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acid encoding for a histone stem-loop and a poly-A sequence or a polyadenylation signal may code for a pathogen antigen or fragment thereof such as the nucleic acid sequences described in International Patent Publication Nos. WO2013/120499 and WO2013/120628, the contents of both of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acid encoding for a histone stem-loop and a poly-A sequence or a polyadenylation signal may code for a therapeutic protein such as the nucleic acid sequences described in International Patent Publication Nos. WO2013/120497 and WO2013/120629, the contents of both of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acid encoding for a histone stem-loop and a poly-A sequence or a polyadenylation signal may code for a tumor antigen or fragment thereof such as the nucleic acid sequences described in International Patent Publication Nos. WO2013/120500 and WO2013/120627, the contents of both of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acid encoding for a histone stem-loop and a poly-A sequence or a polyadenylation signal may code for an autoimmune self-antigen such as the nucleic acid sequences described in International Patent Publication Nos. WO2013/120498 and WO2013/120626, the contents of both of which are incorporated herein by reference in their entirety. mRNA: Triple helices In some embodiments, nucleic acids of the present disclosure (e.g., the mRNA of the present disclosure) may include a triple helix on the 3’ end of the nucleic acid. The 3’ end of the nucleic acids of the present disclosure may include a triple helix alone or in combination with a poly-A tail. In some embodiments, the nucleic acid of the present disclosure may include at least a first and a second U-rich region, a conserved stem-loop region between the first and second region and an A-rich region. The first and second U-rich region and the A- rich region may associate to form a triple helix on the 3’ end of the nucleic acid. This triple helix may stabilize the nucleic acid, enhance the translational efficiency of the nucleic acid and/or protect the 3’ end from degradation. Triple helices include, but are not limited to, the triple helix sequence of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), MEN-β and polyadenylated nuclear (PAN) RNA (See Wilusz et al., Genes & Development 201226:2392-2407; herein incorporated by reference in its entirety). In some embodiments, the triple helix may be formed from the cleavage of a MALAT1 sequence prior to the cloverleaf structure. While not meaning to be bound by theory, MALAT1 is a long non-coding RNA which, when cleaved, forms a triple helix and a tRNA-like cloverleaf structure. The MALAT1 transcript then localizes to nuclear speckles and the tRNA-like cloverleaf localizes to the cytoplasm (Wilusz et al., Cell 2008135(5): 919-932; incorporated herein by reference in its entirety). As a non-limiting example, the terminal end of the nucleic acid of the present disclosure including the MALAT1 sequence can then form a triple helix structure, after RNaseP cleavage from the cloverleaf structure, which stabilizes the nucleic acid (Peart et al., Non-mRNA 3’ end formation: how the other half lives; WIREs RNA 2013; incorporated herein by reference in its entirety). In some embodiments, the nucleic acids or mRNA described herein include a MALAT1 sequence. In some embodiments, the nucleic acids or mRNA may be polyadenylated. In yet another embodiment, the nucleic acids or mRNA is not polyadenylated but has an increased resistance to degradation compared to unaltered nucleic acids or mRNA. In some embodiments, the nucleic acids of the present disclosure may include a MALAT1 sequence in the second flanking region (e.g., the 3’-UTR). As a non-limiting example, the MALAT1 sequence may be human or mouse. mRNA: Translation enhancer elements (TEEs) The term “translational enhancer element” or “translation enhancer element” (herein collectively referred to as “TEE”) refers to sequences that increase the amount of polypeptide or protein produced from an mRNA. TEEs are conserved elements in the UTR which can promote translational activity of a nucleic acid such as, but not limited to, cap-dependent or cap-independent translation. The conservation of these sequences has been previously shown by Panek et al. (Nucleic Acids Research, 2013, 1-10; incorporated herein by reference in its entirety) across 14 species including humans. In some embodiments, the 5’-UTR of the mRNA includes at least one TEE. The TEE may be located between the transcription promoter and the start codon. The mRNA with at least one TEE in the 5’-UTR may include a cap at the 5’-UTR. Further, at least one TEE may be located in the 5’-UTR of mRNA undergoing cap-dependent or cap-independent translation. The TEEs known may be in the 5′-leader of the Gtx homeodomain protein (Chappell et al., Proc. Natl. Acad. Sci. USA 101:9590-9594, 2004, incorporated herein by reference in their entirety). In another non-limiting example, TEEs are disclosed as SEQ ID NOs: 1-35 in US Patent Publication No. US20090226470, SEQ ID NOs: 1-35 in US Patent Publication No. US20130177581, SEQ ID NOs: 1-35 in International Patent Publication No. WO2009075886, SEQ ID NOs: 1-5, and 7-645 in International Patent Publication No. WO2012009644, SEQ ID NO: 1 in International Patent Publication No. WO1999024595, SEQ ID NO: 1 in US Patent No. US6310197, and SEQ ID NO: 1 in US Patent No. US6849405, each of which is incorporated herein by reference in its entirety. The TEE may be an internal ribosome entry site (IRES), HCV-IRES or an IRES element such as, but not limited to, those described in US Patent No. US7468275, US Patent Publication Nos. US20070048776 and US20110124100 and International Patent Publication Nos. WO2007025008 and WO2001055369, each of which is incorporated herein by reference in its entirety. The IRES elements may include, but are not limited to, the Gtx sequences (e.g., Gtx9-nt, Gtx8-nt, Gtx7-nt) described by Chappell et al. (Proc. Natl. Acad. Sci. USA 101:9590-9594, 2004) and Zhou et al. (PNAS 102:6273- 6278, 2005) and in US Patent Publication Nos. US20070048776 and US20110124100 and International Patent Publication No. WO2007025008, each of which is incorporated herein by reference in its entirety. Additional exemplary TEEs are disclosed in US Patent Nos. US6310197, US6849405, US7456273, US7183395; US Patent Publication Nos. US20090226470, US20070048776, US20110124100, US20090093049, US20130177581; International Patent Publication Nos. WO2009075886, WO2007025008, WO2012009644, WO2001055371 WO1999024595; and European Patent Publications Nos. EP2610341A1 and EP2610340A1; each of which is incorporated herein by reference in its entirety. In some embodiments, the polynucleotides, primary constructs, alternative nucleic acids and/or mRNA may include at least one TEE that is described in International Patent Publication Nos. WO1999024595, WO2012009644, WO2009075886, WO2007025008, WO1999024595, European Patent Publication Nos. EP2610341A1 and EP2610340A1, US Patent Nos. US6310197, US6849405, US7456273, US7183395, US Patent Publication No. US20090226470, US20110124100, US20070048776, US20090093049, and US20130177581 each of which is incorporated herein by reference in its entirety. The TEE may be located in the 5’-UTR of the mRNA. In some embodiments, the polynucleotides, primary constructs, alternative nucleic acids and/or mmRNA may include at least one TEE that has at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity with the TEEs described in US Patent Publication Nos. US20090226470, US20070048776, US20130177581 and US20110124100, International Patent Publication Nos. WO1999024595, WO2012009644, WO2009075886 and WO2007025008, European Patent Publication No. EP2610341A1 and EP2610340A1, and US Patent Nos. US6310197, US6849405, US7456273, and US7183395, each of which is incorporated herein by reference in its entirety. Multiple copies of a specific TEE can be present in mRNA. The TEEs in the translational enhancer polynucleotides can be organized in one or more sequence segments. A sequence segment can harbor one or more of the specific TEEs exemplified herein, with each TEE being present in one or more copies. When multiple sequence segments are present in a translational enhancer polynucleotide, they can be homogenous or heterogeneous. Thus, the multiple sequence segments in a translational enhancer polynucleotide can harbor identical or different types of the specific TEEs exemplified herein, identical or different number of copies of each of the specific TEEs, and/or identical or different organization of the TEEs within each sequence segment. In some embodiments, the 5’-UTR of the mRNA may include at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55 or more than 60 TEE sequences. The TEE sequences in the 5’-UTR of mRNA of the present disclosure may be the same or different TEE sequences. The TEE sequences may be in a pattern such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than three times. In these patterns, each letter, A, B, or C represent a different TEE sequence at the nucleotide level. In some embodiments, the 5’-UTR may include a spacer to separate two TEE sequences. As a non-limiting example, the spacer may be a 15 nucleotide spacer and/or other spacers known in the art. As another non-limiting example, the 5’-UTR may include a TEE sequence-spacer module repeated at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times and at least 9 times, or more than 9 times in the 5’-UTR. In some embodiments, the TEE in the 5’-UTR of the mRNA of the present disclosure may include at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or more than 99% of the TEE sequences disclosed in US Patent Publication Nos. US20090226470, US20070048776, US20130177581 and US20110124100, International Patent Publication Nos. WO1999024595, WO2012009644, WO2009075886 and WO2007025008, European Patent Publication Nos. EP2610341A1 and EP2610340A1, and US Patent No. US6310197, US6849405, US7456273, and US7183395 each of which is incorporated herein by reference in its entirety. In some embodiments, the TEE in the 5’-UTR of the mRNA of the present disclosure may include a 5-30 nucleotide fragment, a 5-25 nucleotide fragment, a 5-20 nucleotide fragment, a 5-15 nucleotide fragment, a 5-10 nucleotide fragment of the TEE sequences disclosed in US Patent Publication Nos. US20090226470, US20070048776, US20130177581, and US20110124100, International Patent Publication No. WO1999024595, WO2012009644, WO2009075886, and WO2007025008, European Patent Publication No. EP2610341A1 and EP2610340A1, and US Patent Nos. US6310197, US6849405, US7456273, and US7183395; each of which is incorporated herein by reference in its entirety. In some embodiments, the TEE in the 5’-UTR of the mRNA of the present disclosure may include at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or more than 99% of the TEE sequences disclosed in Chappell et al. (Proc. Natl. Acad. Sci. USA 101:9590-9594, 2004) and Zhou et al. (PNAS 102:6273-6278, 2005), in Supplemental Table 1 and in Supplemental Table 2 disclosed by Wellensiek et al. (Genome-wide profiling of human cap- independent translation-enhancing elements, Nature Methods, 2013; DOI:10.1038/NMETH.2522); each of which is herein incorporated by reference in its entirety. In some embodiments, the TEE in the 5’-UTR of the polynucleotides, primary constructs, alternative nucleic acids and/or mRNA of the present disclosure may include a 5-30 nucleotide fragment, a 5-25 nucleotide fragment, a 5-20 nucleotide fragment, a 5-15 nucleotide fragment, a 5-10 nucleotide fragment of the TEE sequences disclosed in Chappell et al. (Proc. Natl. Acad. Sci. USA 101:9590-9594, 2004) and Zhou et al. (PNAS 102:6273-6278, 2005), in Supplemental Table 1 and in Supplemental Table 2 disclosed by Wellensiek et al. (Genome-wide profiling of human cap-independent translation-enhancing elements, Nature Methods, 2013; DOI:10.1038/NMETH.2522); each of which is incorporated herein by reference in its entirety. In some embodiments, the TEE used in the 5’-UTR of the mRNA of the present disclosure is an IRES sequence such as, but not limited to, those described in US Patent No. US7468275 and International Patent Publication No. WO2001055369, each of which is incorporated herein by reference in its entirety. In some embodiments, the TEEs used in the 5’-UTR of the mRNA of the present disclosure may be identified by the methods described in US Patent Publication Nos. US20070048776 and US20110124100 and International Patent Publication Nos. WO2007025008 and WO2012009644, each of which is incorporated herein by reference in its entirety. In some embodiments, the TEEs used in the 5’-UTR of the mRNA of the present disclosure may be a transcription regulatory element described in US Patent Nos. US7456273 and US7183395, US Patent Publication No. US20090093049, and International Publication No. WO2001055371, each of which is incorporated herein by reference in its entirety. The transcription regulatory elements may be identified by methods known in the art, such as, but not limited to, the methods described in US Patent Nos. US7456273 and US7183395, US Patent Publication No. US20090093049, and International Publication No. WO2001055371, each of which is incorporated herein by reference in its entirety. In yet another embodiment, the TEE used in the 5’-UTR of the mRNA of the present disclosure is an oligonucleotide or portion thereof as described in US Patent No. US7456273 and US7183395, US Patent Publication No. US20090093049, and International Publication No. WO2001055371, each of which is incorporated herein by reference in its entirety. The 5’-UTR including at least one TEE described herein may be incorporated in a monocistronic sequence such as, but not limited to, a vector system or a nucleic acid vector. As a non-limiting example, the vector systems and nucleic acid vectors may include those described in US Patent Nos.7456273 and US7183395, US Patent Publication Nos. US20070048776, US20090093049, and US20110124100 and International Patent Publication Nos. WO2007025008 and WO2001055371, each of which is incorporated herein by reference in its entirety. In some embodiments, the TEEs described herein may be located in the 5’-UTR and/or the 3’-UTR of the mRNA. The TEEs located in the 3’-UTR may be the same and/or different than the TEEs located in and/or described for incorporation in the 5’- UTR. In some embodiments, the 3’-UTR of the mRNA may include at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55 or more than 60 TEE sequences. The TEE sequences in the 3’-UTR of the polynucleotides, primary constructs, alternative nucleic acids and/or mRNA of the present disclosure may be the same or different TEE sequences. The TEE sequences may be in a pattern such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than three times. In these patterns, each letter, A, B, or C represent a different TEE sequence at the nucleotide level. In some embodiments, the 3’-UTR may include a spacer to separate two TEE sequences. As a non-limiting example, the spacer may be a 15-nucleotide spacer and/or other spacers known in the art. As another non-limiting example, the 3’-UTR may include a TEE sequence-spacer module repeated at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times and at least 9 times or more than 9 times in the 3’-UTR. Regions having a 5′ Cap The disclosure also includes a polynucleotide that comprises both a 5′ cap and a polynucleotide of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide to be expressed). The 5′ cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns during mRNA splicing. Endogenous mRNA molecules can be 5′-end capped generating a 5′-ppp-5′- triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap can then be methylated to generate an N7-methyl-guanylate residue. The ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5′ end of the mRNA can optionally also be 2′-O-methylated.5′-decapping through hydrolysis and cleavage of the guanylate cap structure can target a nucleic acid molecule, such as an mRNA molecule, for degradation. In some embodiments, the polynucleotides of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide) incorporate a cap moiety. In any of the embodiments disclosed herein, a 5’ terminal cap may terminate at the 3’ end with an A or G, even if not shown in the disclosure below. In some embodiments, polynucleotides of the present disclosure comprise a non- hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides can be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, MA) can be used with α-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides can be used such as α-methyl-phosphonate and seleno-phosphate nucleotides. Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and/or 5′-anteterminal nucleotides of the polynucleotide (as mentioned above) on the 2′-hydroxyl group of the sugar ring. Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as a polynucleotide that functions as an mRNA molecule. Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e., endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs can be chemically (i.e., non-enzymatically) or enzymatically synthesized and/or linked to the polynucleotides of the present disclosure. For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′-triphosphate-5′- guanosine (m7G-3′mppp-G; which can equivalently be designated 3′ O-Me- m7G(5′)ppp(5′)G). The 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped polynucleotide. The N7- and 3′-O-methlyated guanine provides the terminal moiety of the capped polynucleotide. Another exemplary cap is mCAP, which is similar to ARCA but has a 2′-O-methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine, m7Gm-ppp-G). Another exemplary cap is m7G-ppp-Gm-A (i.e., N7,guanosine-5′-triphosphate-2′- O-dimethyl-guanosine-adenosine). In some embodiments, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog can be modified at different phosphate positions with a boranophosphate group or a phosphoroselenoate group such as the dinucleotide cap analogs described in U.S. Patent No. US 8,519,110, the contents of which are herein incorporated by reference in its entirety. In some embodiments, the cap is a cap analog is a N7-(4-chlorophenoxyethyl) substituted dinucleotide form of a cap analog known in the art and/or described herein. Non-limiting examples of a N7-(4-chlorophenoxyethyl) substituted dinucleotide form of a cap analog include a N7-(4-chlorophenoxyethyl)-G(5′)ppp(5′)G and a N7-(4- chlorophenoxyethyl)-m3′-OG(5′)ppp(5′)G cap analog (See, e.g., the various cap analogs and the methods of synthesizing cap analogs described in Kore et al. Bioorganic & Medicinal Chemistry 201321:4570-4574; the contents of which are herein incorporated by reference in its entirety). In some embodiments, a cap analog of the present disclosure is a 4-chloro/bromophenoxyethyl analog. Polynucleotides of the present disclosure can also be capped post-manufacture (whether IVT or chemical synthesis), using enzymes, in order to generate more authentic 5′-cap structures. As used herein, the phrase "more authentic" refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a "more authentic" feature is better representative of an endogenous, wild-type, natural or physiological cellular function and/or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non-limiting examples of more authentic 5′cap structures of the present disclosure are those that, among other things, have enhanced binding of cap binding proteins, increased half-life, reduced susceptibility to 5′ endonucleases and/or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild- type, natural or physiological 5′cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of a polynucleotide and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl. Such a structure is termed the Cap1 structure. This cap results in a higher translational- competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5′)ppp(5′)N1pN2p (cap 0), 7mG(5′)ppp(5′)N1mpNp (cap 1), 7mG(5′)-ppp(5′)N1mpN2mp (cap 2) , and m(7)Gpppm(3)(6,6,2')Apm(2')Apm(2')Cpm(2)(3,2')Up (cap 4). As a non-limiting example, capping chimeric polynucleotides post-manufacture can be more efficient as nearly 100% of the chimeric polynucleotides can be capped. This is in contrast to ~80% when a cap analog is linked to a chimeric polynucleotide in the course of an in vitro transcription reaction. According to the present disclosure, 5′ terminal caps can include endogenous caps or cap analogs. According to the present disclosure, a 5′ terminal cap can comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. Also provided herein are exemplary caps including those that can be used in co- transcriptional capping methods for ribonucleic acid (RNA) synthesis, using RNA polymerase, e.g., wild type RNA polymerase or variants thereof, e.g., such as those variants described herein. In some embodiments, caps can be added when RNA is produced in a “one-pot” reaction, without the need for a separate capping reaction. Thus, the methods, in some embodiments, comprise reacting a polynucleotide template with an RNA polymerase variant, nucleoside triphosphates, and a cap analog under in vitro transcription reaction conditions to produce RNA transcript. As used here the term “cap” includes the inverted G nucleotide and can comprise one or more additional nucleotides 3’ of the inverted G nucleotide, e.g., 1, 2, 3, or more nucleotides 3’ of the inverted G nucleotide and 5’ to the 5’ UTR, e.g., a 5’ UTR described herein. Exemplary caps comprise a sequence of GG, GA, or GGA, wherein the underlined, italicized G is an in inverted G nucleotide followed by a 5’-5’-triphosphate group. In some embodiments, a cap comprises a compound of Formula (C-I)

(C-I), or a stereoisomer, tautomer or salt thereof, wherein

ring B₁ is a modified or unmodified Guanine; ring B₂ and ring B₃ each independently is a nucleobase or a modified nucleobase; X₂ is O, S(O)_p, NR₂₄ or CR₂₅R₂₆ in which p is 0, 1, or 2; Y₀ is O or CR₆R₇; Y1 is O, S(O)_n, CR₆R₇, or NR₈, in which n is 0, 1 , or 2; each --- is a single bond or absent, wherein when each --- is a single bond, Yi is O, S(O)_n, CR₆R₇, or NR₈; and when each --- is absent, Y₁ is void; Y₂ is (OP(O)R₄)m in which m is 0, 1, or 2, or -O-(CR₄₀R₄₁)u-Q₀-(CR₄₂R₄₃)v-, in whichQ₀ is a bond, O, S(O)_r, NR₄₄, or CR₄₅R₄₆, r is 0, 1 , or 2, and each of u and v independently is 1, 2, 3 or 4; each R₂ and R₂' independently is halo, LNA, or OR₃; eachR₃ independently is H, C_1-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl and R₃, when being C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, is optionally substituted with one or more of halo, OH and C_1-C₆ alkoxyl that is optionally substituted with one or more OH or OC(O)-C_1-C₆ alkyl; each R₄ and R₄' independently is H, halo, C₁-C₆ alkyl, OH, SH, SeH, or BH₃-; each of R₆, R₇, and R₈, independently, is -Q₁-T₁, in which Q₁ is a bond or C₁-C₃ alkyl linker optionally substituted with one or more of halo, cyano, OH and C_1-C₆ alkoxy, and T₁ is H, halo, OH, COOH, cyano, or R_s1, in which R_s1 is C₁-C₃ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁- C₆ alkoxyl, C(O)O-C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, NR₃₁R₃₂, (NR₃₁R₃₂R₃₃)⁺, 4 to 12- membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and Rs1 is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C₁-C₆ alkyl, COOH, C(O)O-C₁-C₆ alkyl, cyano, C₁- C₆ alkoxyl, NR₃₁R₃₂, (NR31R32R33)⁺, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each of R₁₀, R₁₁, R₁₂, R₁₃ R₁₄, and R₁₅, independently, is -Q₂-T₂, in which Q₂ is a bond or C₁-C₃ alkyl linker optionally substituted with one or more of halo, cyano, OH and C₁- C₆ alkoxy, and T₂ is H, halo, OH, NH₂, cyano, NO₂, N₃, R_s2, or O R_s2, in which R_s2 is C_1- C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, NHC(O)-C₁-C₆ alkyl, NR₃₁R₃₂, (NR₃₁R₃₂R₃₃)⁺, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R_s2 is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C_1-C₆ alkyl, COOH, C(O)O-C_1-C₆ alkyl, cyano, C₁ - C₆ alkoxyl, NR₃₁R₃₂, (NR₃₁R₃₂R₃₃)⁺, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6- membered heteroaryl; or alternatively R₁₂ together with R₁₄ is oxo, or R₁₃ together with R₁₅ is oxo, each of R₂₀, R₂₁, R₂₂, and R₂₃ independently is -Q₃-T₃, in which Q₃ is a bond or C₁-C₃ alkyl linker optionally substituted with one or more of halo, cyano, OH and C_1-C₆ alkoxy, and T ₃ is H, halo, OH, NH₂, cyano, NO₂, N₃, R_S3, or O R_S3, in which R_S3 is C_1-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, NHC(O)-C₁-C₆ alkyl, mono- C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered heteroaryl, and R_S3 is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C_1-C₆ alkyl, COOH, C(O)O-C_1-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each of R₂₄, R₂₅, and R₂₆ independently is H or C_1-C₆ alkyl; each of R₂₇ and R₂₈ independently is H or OR₂₉; or R₂₇ and R₂₈ together form O-R₃₀-O; each R₂₉ independently is H, C_1-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl and R₂₉, when being C_1-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, is optionally substituted with one or more of halo, OH and C₁-C₆ alkoxyl that is optionally substituted with one or more OH or OC(O)-C₁-C₆ alkyl; R₃₀ is C_1-C₆ alkylene optionally substituted with one or more of halo, OH and C_1-C₆ alkoxyl; each of R₃₁, R₃₂, and R₃₃, independently is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; each of R₄₀, R₄₁, R₄₂, and R₄₃ independently is H, halo, OH, cyano, N₃, OP(O)R₄₇R₄₈, or C₁-C₆ alkyl optionally substituted with one or more OP(O)R₄₇R₄₈, or one R₄₁ and one R43, together with the carbon atoms to which they are attached and Q₀, form C₄-C₁₀ cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 14-membered heteroaryl, and each of the cycloalkyl, heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one or more of OH, halo, cyano, N₃, oxo, OP(O)R₄₇R₄₈, C_1-C₆ alkyl, C_1-C₆ haloalkyl, COOH, C(O)O-C_1-C₆ alkyl, C_1-C₆ alkoxyl, C_1- C₆ haloalkoxyl, amino, mono-C₁-C₆ alkylamino, and di-C₁-C₆ alkylamino; R₄₄ is H, C₁-C₆ alkyl, or an amine protecting group; each of R₄₅ and R₄₆ independently is H, OP(O)R₄₇R₄₈, or C_1-C₆ alkyl optionally substituted with one or more OP(O)R₄₇R₄₈, and each of R₄₇ and R₄₈, independently is H, halo, C₁-C₆ alkyl, OH, SH, SeH, or BH₃. It should be understood that a cap analog, as provided herein, may include any of the cap analogs described in international publication WO 2017/066797, published on 20 April 2017, incorporated by reference herein in its entirety. In some embodiments, the B₂ middle position can be a non-ribose molecule, such as arabinose. In some embodiments R₂ is ethyl-based. Thus, in some embodiments, a cap comprises the following structure:

(C-II). In other embodiments, a cap comprises the following structure:

In yet other embodiments, a cap comprises the following structure:

(C-IV). In still other embodiments, a cap comprises the following structure:

(C-V). In some embodiments, R is an alkyl (e.g., C₁-C₆ alkyl). In some embodiments, R is a methyl group (e.g., C₁ alkyl). In some embodiments, R is an ethyl group (e.g., C₂ alkyl). In some embodiments, a cap comprises a sequence selected from the following sequences: GAA, GAC, GAG, GAU, GCA, GCC, GCG, GCU, GGA , GGC, GGG, GGU, GUA, GUC, GUG, and GUU. In some embodiments, a cap comprises GAA. In some embodiments, a cap comprises GAC. In some embodiments, a cap comprises GAG. In some embodiments, a cap comprises GAU. In some embodiments, a cap comprises GCA. In some embodiments, a cap comprises GCC. In some embodiments, a cap comprises GCG. In some embodiments, a cap comprises GCU. In some embodiments, a cap comprises GGA. In some embodiments, a cap comprises GGC. In some embodiments, a cap comprises GGG. In some embodiments, a cap comprises GGU. In some embodiments, a cap comprises GUA. In some embodiments, a cap comprises GUC. In some embodiments, a cap comprises GUG. In some embodiments, a cap comprises GUU. In some embodiments, a cap comprises a sequence selected from the following sequences: m⁷GpppApA, m⁷GpppApC, m⁷GpppApG, m⁷GpppApU, m⁷GpppCpA, m⁷GpppCpC, m⁷GpppCpG, m⁷GpppCpU, m⁷GpppGpA, m⁷GpppGpC, m⁷GpppGpG, m⁷GpppGpU, m⁷GpppUpA, m⁷GpppUpC, m⁷GpppUpG, and m⁷GpppUpU. In some embodiments, a cap comprises m⁷GpppApA. In some embodiments, a cap comprises m⁷GpppApC. In some embodiments, a cap comprises m⁷GpppApG. In some embodiments, a cap comprises m⁷GpppApU. In some embodiments, a cap comprises m⁷GpppCpA. In some embodiments, a cap comprises m⁷GpppCpC. In some embodiments, a cap comprises m⁷GpppCpG. In some embodiments, a cap comprises m⁷GpppCpU. In some embodiments, a cap comprises m⁷GpppGpA. In some embodiments, a cap comprises m⁷GpppGpC. In some embodiments, a cap comprises m⁷GpppGpG. In some embodiments, a cap comprises m⁷GpppGpU. In some embodiments, a cap comprises m⁷GpppUpA. In some embodiments, a cap comprises m⁷GpppUpC. In some embodiments, a cap comprises m⁷GpppUpG. In some embodiments, a cap comprises m⁷GpppUpU. A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷G_{3 'OMe}pppApA, m⁷G_{3 'OMe}pppApC, m⁷G_{3 'OMe}pppApG, m⁷G_{3 'OMe}pppApU, m⁷G_{3 'OMe}pppCpA, m⁷G_{3 'OMe}pppCpC, m⁷G_{3 'OMe}pppCpG, m⁷G_{3 'OMe}pppCpU, m⁷G_{3 'OMe}pppGpA, m⁷G_{3 'OMe}pppGpC, m⁷G_{3 'OMe}pppGpG, m⁷G_{3 'OMe}pppGpU, m⁷G_{3 'OMe}pppUpA, m⁷G_{3 'OMe}pppUpC, m⁷G_{3 'OMe}pppUpG, and m⁷G_{3 'OMe}pppUpU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppApA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppApC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppApG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppApU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppCpA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppCpC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppCpG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppCpU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppGpA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppGpC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppGpG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppGpU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppUpA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppUpC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppUpG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppUpU. In some embodiments, a cap comprises a sequence selected from the following sequences: m⁷G_{3 'OMe}pppA_{2 'OMe}pA, m⁷G_{3 'OMe}pppA_{2 'OMe}pC, m⁷G_{3 'OMe}pppA_{2 'OMe}pG, m⁷G_{3 'OMe}pppA_{2 'OMe}pU, m⁷G_{3 'OMe}pppC_{2 'OMe}pA, m⁷G_{3 'OMe}pppC_{2 'OMe}pC, m⁷G_{3 'OMe}pppC_{2 'OMe}pG, m⁷G_{3 'OMe}pppC_{2 'OMe}pU, m⁷G_{3 'OMe}pppG_{2 'OMe}pA, m⁷G_{3 'OMe}pppG_{2 'OMe}pC, m⁷G_{3 'OMe}pppG_{2 'OMe}pG, m⁷G_{3 'OMe}pppG_{2 'OMe}pU, m⁷G_{3 'OMe}pppU_{2 'OMe}pA, m⁷G_{3 'OMe}pppU_{2 'OMe}pC, m⁷G_{3 'OMe}pppU_{2 'OMe}pG, and m⁷G_{3 'OMe}pppU_{2 'OMe}pU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppA_{2 'OMe}pA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppA_{2 'OMe}pC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppA_{2 'OMe}pG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppA_{2 'OMe}pU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppC_{2 'OMe}pA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppC_{2 'OMe}pC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppC_{2 'OMe}pG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppC_{2 'OMe}pU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppG_{2 'OMe}pA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppG_{2 'OMe}pC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppG_{2 'OMe}pG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppG_{2 'OMe}pU. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppU_{2 'OMe}pA. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppU_{2 'OMe}pC. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppU_{2 'OMe}pG. In some embodiments, a cap comprises m⁷G_{3 'OMe}pppU_{2 'OMe}pU. A cap, in still other embodiments, comprises a sequence selected from the following sequences: m⁷GpppA_{2 'OMe}pA, m⁷GpppA_{2 'OMe}pC, m⁷GpppA_{2 'OMe}pG, m⁷GpppA_{2 'OMe}pU, m⁷GpppC_{2 'OMe}pA, m⁷GpppC_{2 'OMe}pC, m⁷GpppC_{2 'OMe}pG, m⁷GpppC_{2 'OMe}pU, m⁷GpppG_{2 'OMe}pA, m⁷GpppG_{2 'OMe}pC, m⁷GpppG_{2 'OMe}pG, m⁷GpppG_{2 'OMe}pU, m⁷GpppU_{2 'OMe}pA, m⁷GpppU_{2 'OMe}pC, m⁷GpppU_{2 'OMe}pG, and m⁷GpppU_{2 'OMe}pU. In some embodiments, a cap comprises m⁷GpppA_{2 'OMe}pA. In some embodiments, a cap comprises m⁷GpppA_{2 'OMe}pC. In some embodiments, a cap comprises m⁷GpppA_{2 'OMe}pG. In some embodiments, a cap comprises m⁷GpppA_{2 'OMe}pU. In some embodiments, a cap comprises m⁷GpppC_{2 'OMe}pA. In some embodiments, a cap comprises m⁷GpppC_{2 'OMe}pC. In some embodiments, a cap comprises m⁷GpppC_{2 'OMe}pG. In some embodiments, a trinucleotide cap comprises m⁷GpppC_{2 'OMe}pU. In some embodiments, a cap comprises m⁷GpppG_{2 'OMe}pA. In some embodiments, a cap comprises m⁷GpppG_{2 'OMe}pC. In some embodiments, a cap comprises m⁷GpppG_{2 'OMe}pG. In some embodiments, a cap comprises m⁷GpppG_{2 'OMe}pU. In some embodiments, a cap comprises m⁷GpppU_{2 'OMe}pA. In some embodiments, a cap comprises m⁷GpppU_{2 'OMe}pC. In some embodiments, a cap comprises m⁷GpppU_{2 'OMe}pG. In some embodiments, a cap comprises m⁷GpppU_{2 'OMe}pU. In some embodiments, a cap comprises m⁷Gpppm⁶A_2’OmepG. In some embodiments, a cap comprises m⁷Gpppe⁶A_2’OmepG. In some embodiments, a cap comprises GAG. In some embodiments, a cap comprises GCG. In some embodiments, a cap comprises GUG. In some embodiments, a cap comprises GGG. In some embodiments, a cap comprises any one of the following structures:

.

In some embodiments, the cap comprises ^m7GpppN₁N₂N₃, where N₁, N₂, and N₃ are optional (i.e., can be absent or one or more can be present) and are independently a natural, a modified, or an unnatural nucleoside base. In some embodiments, ^m7G is further methylated, e.g., at the 3’ position. In some embodiments, the ^m7G comprises an O-methyl at the 3’ position. In some embodiments N₁, N₂, and N₃ if present, optionally, are independently an adenine, a uracil, a guanidine, a thymine, or a cytosine. In some embodiments, one or more (or all) of N₁, N₂, and N₃, if present, are methylated, e.g., at the 2’ position. In some embodiments, one or more (or all) of N₁, N₂, and N_3, if present have an O-methyl at the 2’ position. In some embodiments, the cap comprises the following structure:

(C-IX) wherein B₁, B₂, and B₃ are independently a natural, a modified, or an unnatural nucleoside based; and R₁, R₂, R₃, and R₄ are independently OH or O-methyl. In some embodiments, R₃ is O-methyl and R₄ is OH. In some embodiments, R₃ and R₄ are O- methyl. In some embodiments, R₄ is O-methyl. In some embodiments, R₁ is OH, R₂ is OH, R₃ is O-methyl, and R₄ is OH. In some embodiments, R₁ is OH, R₂ is OH, R₃ is O- methyl, and R₄ is O-methyl. In some embodiments, at least one of R₁ and R₂ is O- methyl, R₃ is O-methyl, and R₄ is OH. In some embodiments, at least one of R₁ and R₂ is O-methyl, R₃ is O-methyl, and R₄ is O-methyl. In some embodiments, B₁, B₃, and B₃ are natural nucleoside bases. In some embodiments, at least one of B₁, B₂, and B₃ is a modified or unnatural base. In some embodiments, at least one of B₁, B₂, and B₃ is N6-methyladenine. In some embodiments, B₁ is adenine, cytosine, thymine, or uracil. In some embodiments, B₁ is adenine, B₂ is uracil, and B₃ is adenine. In some embodiments, R₁ and R₂ are OH, R₃ and R₄ are O-methyl, B₁ is adenine, B₂ is uracil, and B₃ is adenine. In some embodiments the cap comprises a sequence selected from the following sequences: GAAA, GACA, GAGA, GAUA, GCAA, GCCA, GCGA, GCUA, GGAA, GGCA, GGGA, GGUA, GUCA, and GUUA. In some embodiments the cap comprises a sequence selected from the following sequences: GAAG, GACG, GAGG, GAUG, GCAG, GCCG, GCGG, GCUG, GGAG, GGCG, GGGG, GGUG, GUCG, GUGG, and GUUG. In some embodiments the cap comprises a sequence selected from the following sequences: GAAU, GACU, GAGU, GAUU, GCAU, GCCU, GCGU, GCUU, GGAU, GGCU, GGGU, GGUU, GUAU, GUCU, GUGU, and GUUU. In some embodiments the cap comprises a sequence selected from the following sequences: GAAC, GACC, GAGC, GAUC, GCAC, GCCC, GCGC, GCUC, GGAC, GGCC, GGGC, GGUC, GUAC, GUCC, GUGC, and GUUC. A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷G_{3 'OMe}pppApApN, m⁷G_{3 'OMe}pppApCpN, m⁷G_{3 'OMe}pppApGpN, m⁷G_{3 'OMe}pppApUpN, m⁷G_{3 'OMe}pppCpApN, m⁷G_{3 'OMe}pppCpCpN, m⁷G_{3 'OMe}pppCpGpN, m⁷G_{3 'OMe}pppCpUpN, m⁷G_{3 'OMe}pppGpApN, m⁷G_{3 'OMe}pppGpCpN, m⁷G_{3 'OMe}pppGpGpN, m⁷G_{3 'OMe}pppGpUpN, m⁷G_{3 'OMe}pppUpApN, m⁷G_{3 'OMe}pppUpCpN, m⁷G_{3 'OMe}pppUpGpN, and m⁷G_{3 'OMe}pppUpUpN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷G_{3 'OMe}pppA_{2 'OMe}pApN, m⁷G_{3 'OMe}pppA_{2 'OMe}pCpN, m⁷G_{3 'OMe}pppA_{2 'OMe}pGpN, m⁷G_{3 'OMe}pppA_{2 'OMe}pUpN, m⁷G_{3 'OMe}pppC_{2 'OMe}pApN, m⁷G_{3 'OMe}pppC_{2 'OMe}pCpN, m⁷G_{3 'OMe}pppC_{2 'OMe}pGpN, m⁷G_{3 'OMe}pppC_{2 'OMe}pUpN, m⁷G_{3 'OMe}pppG_{2 'OMe}pApN, m⁷G_{3 'OMe}pppG_{2 'OMe}pCpN, m⁷G_{3 'OMe}pppG_{2 'OMe}pGpN, m⁷G_{3 'OMe}pppG_{2 'OMe}pUpN, m⁷G_{3 'OMe}pppU_{2 'OMe}pApN, m⁷G_{3 'OMe}pppU_{2 'OMe}pCpN, m⁷G_{3 'OMe}pppU_{2 'OMe}pGpN, and m⁷G_{3 'OMe}pppU_{2 'OMe}pUpN, where N is a natural, a modified or an unnatural nucleoside base A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷GpppA_{2 'OMe}pApN, m⁷GpppA_{2 'OMe}pCpN, m⁷GpppA_{2 'OMe}pGpN, m⁷GpppA_{2 'OMe}pUpN, m⁷GpppC_{2 'OMe}pApN, m⁷GpppC_{2 'OMe}pCpN, m⁷GpppC_{2 'OMe}pGpN, m⁷GpppC_{2 'OMe}pUpN, m⁷GpppG_{2 'OMe}pApN, m⁷GpppG_{2 'OMe}pCpN, m⁷GpppG_{2 'OMe}pGpN, m⁷GpppG_{2 'OMe}pUpN, m⁷GpppU_{2 'OMe}pApN, m⁷GpppU_{2 'OMe}pCpN, m⁷GpppU_{2 'OMe}pGpN, and m⁷GpppU_{2 'OMe}pUpN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷G_{3 'OMe}pppA_{2 'OMe}pA_{2 'OMe}pN, m⁷G_{3 'OMe}pppA_{2 'OMe}pC_{2 'OMe}pN, m⁷G_{3 'OMe}pppA_{2 'OMe}pG_{2 'OMe}pN, m⁷G_{3 'OMe}pppA_{2 'OMe}pU_{2 'OMe}pN, m⁷G_{3 'OMe}pppC_{2 'OMe}pA_{2 'OMe}pN, m⁷G_{3 'OMe}pppC_{2 'OMe}pC_{2 'OMe}pN, m⁷G_{3 'OMe}pppC_{2 'OMe}pG_{2 'OMe}pN, m⁷G_{3 'OMe}pppC_{2 'OMe}pU_{2 'OMe}pN, m⁷G_{3 'OMe}pppG_{2 'OMe}pA_{2 'OMe}pN, m⁷G_{3 'OMe}pppG_{2 'OMe}pC_{2 'OMe}pN, m⁷G_{3 'OMe}pppG_{2 'OMe}pG_{2 'OMe}pN, m⁷G_{3 'OMe}pppG_{2 'OMe}pU_{2 'OMe}pN, m⁷G_{3 'OMe}pppU_{2 'OMe}pA_{2 'OMe}pN, m⁷G_{3 'OMe}pppU_{2 'OMe}pC_{2 'OMe}pN, m⁷G_{3 'OMe}pppU_{2 'OMe}pG_{2 'OMe}pN, and m⁷G_{3 'OMe}pppU_{2 'OMe}pU_{2 'OMe}pN, where N is a natural, a modified, or an unnatural nucleoside base. A cap, in some embodiments, comprises a sequence selected from the following sequences: m⁷GpppA_{2 'OMe}pA_{2 'OMe}pN, m⁷GpppA_{2 'OMe}pC_{2 'OMe}pN, m⁷GpppA_{2 'OMe}pG_{2 'OMe}pN, m⁷GpppA_{2 'OMe}pU_{2 'OMe}pN, m⁷GpppC_{2 'OMe}pA_{2 'OMe}pN, m⁷GpppC_{2 'OMe}pC_{2 'OMe}pN, m⁷GpppC_{2 'OMe}pG_{2 'OMe}pN, m⁷GpppC_{2 'OMe}pU_{2 'OMe}pN, m⁷GpppG_{2 'OMe}pA_{2 'OMe}pN, m⁷GpppG_{2 'OMe}pC_{2 'OMe}pN, m⁷GpppG_{2 'OMe}pG_{2 'OMe}pN, m⁷GpppG_{2 'OMe}pU_{2 'OMe}pN, m⁷GpppU_{2 'OMe}pA_{2 'OMe}pN, m⁷GpppU_{2 'OMe}pC_{2 'OMe}pN, m⁷GpppU_{2 'OMe}pG_{2 'OMe}pN, and m⁷GpppU_{2 'OMe}pU_{2 'OMe}pN, where N is a natural, a modified, or an unnatural nucleoside base. In some embodiments, a cap comprises GGAG. In some embodiments, a cap comprises the following structure:

In some embodiments, the mRNA comprises a m7GpppGmAG cap. Poly-A Tails In some embodiments, the polynucleotides of the present disclosure (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide) further comprise a poly-A tail. In some embodiments, terminal groups on the poly-A tail can be incorporated for stabilization. In some embodiments, a poly-A tail comprises des-3′ hydroxyl tails. During RNA processing, a long chain of adenine nucleotides (poly-A tail) can be added to a polynucleotide (e.g., an mRNA molecule) in order to increase stability. Immediately after transcription, the 3′ end of the transcript can be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long. In some embodiments, the poly-A tail is 100 nucleotides in length (SEQ ID NO: 140). PolyA tails can also be added after the construct is exported from the nucleus. According to the present disclosure, terminal groups on the poly A tail can be incorporated for stabilization. Polynucleotides of the present disclosure can include des- 3′ hydroxyl tails. They can also include structural moieties or 2'-O-methyl modifications as taught by Junjie Li, et al. (Current Biology, vol.15, 1501–1507, August 23, 2005), the contents of which are incorporated herein by reference in its entirety). The polynucleotides of the present disclosure can be designed to encode transcripts with alternative polyA tail structures including histone mRNA. According to Norbury, "Terminal uridylation has also been detected on human replication-dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3ʹ poly(A) tail, the function of which is instead assumed by a stable stem–loop structure and its cognate stem–loop binding protein (SLBP); the latter carries out the same functions as those of PABP on polyadenylated mRNAs" (Norbury, "Cytoplasmic RNA: a case of the tail wagging the dog," Nature Reviews Molecular Cell Biology; AOP, published online 29 August 2013; doi:10.1038/nrm3645), the contents of which are incorporated herein by reference in its entirety. Unique poly-A tail lengths provide certain advantages to the polynucleotides of the present disclosure. Generally, the length of a poly-A tail, when present, is greater than 30 nucleotides in length. In some embodiments, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides). In some embodiments, the polynucleotide or region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000). In some embodiments, the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design can be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or feature thereof. The poly-A tail can also be designed as a fraction of the polynucleotides to which it belongs. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of polynucleotides for Poly-A binding protein can enhance expression. Additionally, multiple distinct polynucleotides can be linked together via the PABP (Poly-A binding protein) through the 3′-end using modified nucleotides at the 3′-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12hr, 24hr, 48hr, 72hr and day 7 post-transfection. In some embodiments, the polynucleotides of the present disclosure are designed to include a polyA-G Quartet region. The G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA. In some emodiments, the G-quartet is incorporated at the end of the poly-A tail. The resultant polynucleotide is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production from an mRNA equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone (SEQ ID NO: 141). In some embodiments, the polyA tail comprises an alternative nucleoside, e.g., inverted thymidine. PolyA tails comprising an alternative nucleoside, e.g., inverted thymidine, may be generated as described herein. For instance, mRNA constructs may be modified by ligation to stabilize the poly(A) tail. Ligation may be performed using 0.5-1.5 mg/mL mRNA (5′ Cap1, 3′ A100), 50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM TCEP, 1000 units/mL T4 RNA Ligase 1, 1 mM ATP, 20% w/v polyethylene glycol 8000, and 5:1 molar ratio of modifying oligo to mRNA. Modifying oligo has a sequence of 5’- phosphate-AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine (idT) (SEQ ID NO:142)) (see below). Ligation reactions are mixed and incubated at room temperature (~22°C) for, e.g., 4 hours. Stable tail mRNA are purified by, e.g., dT purification, reverse phase purification, hydroxyapatite purification, ultrafiltration into water, and sterile filtration. The resulting stable tail-containing mRNAs contain the following structure at the 3’end, starting with the polyA region: A100-UCUAGAAAAAAAAAAAAAAAAAAAA- inverted deoxythymidine (SEQ ID NO: 143). Modifying oligo to stabilize tail (5’-phosphate-AAAAAAAAAAAAAAAAAAAA- (inverted deoxythymidine)(SEQ ID NO: 144)):

In some instances, the polyA tail comprises A100-UCUAG-A20-inverted deoxy- thymidine (SEQ ID NO: 143). In some instances, the polyA tail consists of A100- UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO: 143). Start codon region The invention also includes a polynucleotide that comprises both a start codon region and the polynucleotide described herein (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide). In some embodiments, the polynucleotides of the present disclosure can have regions that are analogous to or function like a start codon region. In some embodiments, the translation of a polynucleotide can initiate on a codon that is not the start codon AUG. Translation of the polynucleotide can initiate on an alternative start codon such as, but not limited to, ACG, AGG, AAG, CTG/CUG, GTG/GUG, ATA/AUA, ATT/AUU, TTG/UUG (see Touriol et al. Biology of the Cell 95 (2003) 169-178 and Matsuda and Mauro PLoS ONE, 20105:11; the contents of each of which are herein incorporated by reference in its entirety). As a non-limiting example, the translation of a polynucleotide begins on the alternative start codon ACG. As another non-limiting example, polynucleotide translation begins on the alternative start codon CTG or CUG. As yet another non-limiting example, the translation of a polynucleotide begins on the alternative start codon GTG or GUG. Nucleotides flanking a codon that initiates translation such as, but not limited to, a start codon or an alternative start codon, are known to affect the translation efficiency, the length and/or the structure of the polynucleotide. (See, e.g., Matsuda and Mauro PLoS ONE, 20105:11; the contents of which are herein incorporated by reference in its entirety). Masking any of the nucleotides flanking a codon that initiates translation can be used to alter the position of translation initiation, translation efficiency, length and/or structure of a polynucleotide. In some embodiments, a masking agent can be used near the start codon or alternative start codon in order to mask or hide the codon to reduce the probability of translation initiation at the masked start codon or alternative start codon. Non-limiting examples of masking agents include antisense locked nucleic acids (LNA) polynucleotides and exon-junction complexes (EJCs) (See, e.g., Matsuda and Mauro describing masking agents LNA polynucleotides and EJCs (PLoS ONE, 20105:11); the contents of which are herein incorporated by reference in its entirety). In some embodiments, a masking agent can be used to mask a start codon of a polynucleotide in order to increase the likelihood that translation will initiate on an alternative start codon. In some embodiments, a masking agent can be used to mask a first start codon or alternative start codon in order to increase the chance that translation will initiate on a start codon or alternative start codon downstream to the masked start codon or alternative start codon. In some embodiments, a start codon or alternative start codon can be located within a perfect complement for a miRNA binding site. The perfect complement of a miRNA binding site can help control the translation, length and/or structure of the polynucleotide similar to a masking agent. As a non-limiting example, the start codon or alternative start codon can be located in the middle of a perfect complement for a miRNA binding site. The start codon or alternative start codon can be located after the first nucleotide, second nucleotide, third nucleotide, fourth nucleotide, fifth nucleotide, sixth nucleotide, seventh nucleotide, eighth nucleotide, ninth nucleotide, tenth nucleotide, eleventh nucleotide, twelfth nucleotide, thirteenth nucleotide, fourteenth nucleotide, fifteenth nucleotide, sixteenth nucleotide, seventeenth nucleotide, eighteenth nucleotide, nineteenth nucleotide, twentieth nucleotide or twenty-first nucleotide. In some embodiments, the start codon of a polynucleotide can be removed from the polynucleotide sequence in order to have the translation of the polynucleotide begin on a codon that is not the start codon. Translation of the polynucleotide can begin on the codon following the removed start codon or on a downstream start codon or an alternative start codon. In a non-limiting example, the start codon ATG or AUG is removed as the first 3 nucleotides of the polynucleotide sequence in order to have translation initiate on a downstream start codon or alternative start codon. The polynucleotide sequence where the start codon was removed can further comprise at least one masking agent for the downstream start codon and/or alternative start codons in order to control or attempt to control the initiation of translation, the length of the polynucleotide and/or the structure of the polynucleotide. In some embodiments, the poly(A) tail may be 80 nucleotides, 120 nucleotides, or 160 nucleotides in length. In some embodiments, the poly(A) tail may be 20, 40, 80, 100, 120, 140 or 160 nucleotides in length. In some embodiments, the mRNA comprises a 100 nucleotide poly(A) tail. Stop Codon Region The present disclosure also includes a polynucleotide that comprises both a stop codon region and the polynucleotide described herein (e.g., a polynucleotide comprising a nucleotide sequence encoding an anti-CD28 polypeptide). In some embodiments, the polynucleotides of the present disclosure can include at least two stop codons before the 3′ untranslated region (UTR). The stop codon can be selected from TGA, TAA and TAG in the case of DNA, or from UGA, UAA and UAG in the case of RNA. In some embodiments, the polynucleotides of the present disclosure include the stop codon TGA in the case of DNA, or the stop codon UGA in the case of RNA, and one additional stop codon. In a further embodiment the additional stop codon can be TAA or UAA. In some embodiments, the polynucleotides of the present disclosure include three consecutive stop codons, four stop codons, or more. Combination of mRNA elements Any of the polynucleotides disclosed herein can comprise one, two, three, or all of the following elements: (a) a 5’-UTR, e.g., as described herein; (b) a coding region comprising a stop element (e.g., as described herein); (c) a 3’-UTR (e.g., as described herein) and; optionally (d) a 3’ stabilizing region, e.g., as described herein. Also disclosed herein are LNP compositions comprising the same. In some embodiments, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 5 or a variant or fragment thereof and (b) a coding region comprising a stop element provided herein. In some embodiments, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In some embodiments, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In some embodiments, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 5 or a variant or fragment thereof and (c) a 3’ UTR described in Table 6 or a variant or fragment thereof. In some embodiments, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In some embodiments, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In some embodiments, a polynucleotide of the disclosure comprises (c) a 3’ UTR described in Table 6 or a variant or fragment thereof and (b) a coding region comprising a stop element provided herein. In some embodiments, the polynucleotide comprises a sequence provided in Table 7. In some embodiments, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In some embodiments, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. In some embodiments, a polynucleotide of the disclosure comprises (a) a 5’ UTR described in Table 5 or a variant or fragment thereof; (b) a coding region comprising a stop element provided herein; and (c) a 3’ UTR described in Table 6 or a variant or fragment thereof. In some embodiments, the polynucleotide further comprises a cap structure, e.g., as described herein, or a poly A tail, e.g., as described herein. In some embodiments, the polynucleotide further comprises a 3’ stabilizing region, e.g., as described herein. Table 7 – Exemplary 3’ UTR and stop element sequences

mRNA: Heterologous 5’-UTRs 5’-UTRs of an mRNA of the disclosure may be homologous or heterologous to the coding region found in the mRNA. Multiple 5′ UTRs may be included in mRNA and may be the same or of different sequences. Any portion of the mRNA, including none, may be codon optimized and any may independently contain one or more different structural or chemical alterations, before and/or after codon optimization. Shown in Lengthy Table 21 in International Patent Publication No. WO 2014/081507, and in Lengthy Table 21 and in Table 22 in International Patent Publication No. WO 2014/081507, the contents of each of which are incorporated herein by reference in their entirety, is a listing of the start and stop site of mRNAs. In Table 21 each 5’-UTR (5’-UTR-005 to 5’-UTR 68511) is identified by its start and stop site relative to its native or wild type (homologous) transcript (ENST; the identifier used in the ENSEMBL database). To alter one or more properties of the mRNA of the disclosure, 5’-UTRs which are heterologous to the coding region of the mRNA are engineered into the mRNA. The mRNA (e.g., an mRNA in a composition described herein) is administered to cells, tissue, or organisms, and outcomes such as protein level, localization, and/or half-life are measured to evaluate the beneficial effects the heterologous 5’-UTR may have on mRNA. Variants of the 5’ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.5’-UTRs may also be codon- optimized or altered in any manner described herein. Polynucleotides Comprising an mRNA Encoding a Disclosed Anti-CD28 Antibody, Antigen-Binding Fragment, or Binding Protein In some embodiments, a polynucleotide of the present disclosure, for example a polynucleotide comprising an mRNA nucleotide sequence encoding an anti-CD28 antibody, antigen-binding fragment, or binding protein, comprises from 5′ to 3′ end: (i) a 5′ cap such as provided above; (ii) a 5′ UTR, such as the sequences provided above; (iii) an ORF encoding a disclosed anti-CD28 polypeptide; (iv) at least one stop codon; (v) a 3′ UTR, such as the sequences provided above; and (vi) a poly-A tail provided above. mRNA: RNA motifs for RNA binding proteins RNA binding proteins (RBPs) can regulate numerous aspects of co- and post- transcription gene expression, such as, but not limited to, RNA splicing, localization, translation, turnover, polyadenylation, capping, alteration, export, and localization. RNA-binding domains (RBDs), such as, but not limited to, RNA recognition motif (RR) and hnRNP K-homology (KH) domains, typically regulate the sequence association between RBPs and their RNA targets (Ray et al. Nature 2013.499:172-177; incorporated herein by reference in its entirety). In some embodiments, the canonical RBDs can bind short RNA sequences. In some embodiments, the canonical RBDs can recognize structure RNAs. In some embodiments, to increase the stability of the mRNA of interest, an mRNA encoding HuR is co-transfected or co-injected along with the mRNA of interest into the cells or into the tissue. These proteins can also be tethered to the mRNA of interest in vitro and then administered to the cells together. Poly A tail binding protein, PABP interacts with eukaryotic translation initiation factor eIF4G to stimulate translational initiation. Co-administration of mRNAs encoding these RBPs along with the mRNA drug and/or tethering these proteins to the mRNA drug in vitro and administering the protein-bound mRNA into the cells can increase the translational efficiency of the mRNA. The same concept can be extended to co-administration of mRNA along with mRNAs encoding various translation factors and facilitators as well as with the proteins themselves to influence RNA stability and/or translational efficiency. In some embodiments, the nucleic acids and/or mRNA may include at least one RNA-binding motif such as, but not limited to an RNA-binding domain (RBD). In some embodiments, the RBD may be any of the RBDs, fragments or variants thereof descried by Ray et al. (Nature 2013.499:172-177; incorporated herein by reference in its entirety). In some embodiments, the nucleic acids or mRNA of the present disclosure may include a sequence for at least one RNA-binding domain (RBDs). When the nucleic acids or mRNA of the present disclosure include more than one RBD, the RBDs do not need to be from the same species or even the same structural class. In some embodiments, at least one flanking region (e.g., the 5’-UTR and/or the 3’-UTR) may include at least one RBD. In some embodiments, the first flanking region and the second flanking region may both include at least one RBD. The RBD may be the same or each of the RBDs may have at least 60% (e.g., at least 70%, 80%, or 90%) sequence identity to the other RBD. As a non-limiting example, at least on RBD may be located before, after and/or within the 3’-UTR of the nucleic acid or mRNA of the present disclosure. As another non-limiting example, at least one RBD may be located before or within the first 300 nucleosides of the 3’-UTR. In some embodiments, the nucleic acids and/or mRNA of the present disclosure may include at least one RBD in the first region of linked nucleosides. The RBD may be located before, after, or within a coding region (e.g., the ORF). In another embodiment, the first region of linked nucleosides and/or at least one flanking region may include at least on RBD. As a non-limiting example, the first region of linked nucleosides may include a RBD related to splicing factors and at least one flanking region may include a RBD for stability and/or translation factors. In some embodiments, the nucleic acids and/or mRNA of the present disclosure may include at least one RBD located in a coding and/or non-coding region of the nucleic acids and/or mRNA. In some embodiments, at least one RBD may be incorporated into at least one flanking region to increase the stability of the nucleic acid and/or mRNA of the present disclosure. In some embodiments, an antisense locked nucleic acid (LNA) oligonucleotides and exon-junction complexes (EJCs) may be used in the RNA binding protein motif. The LNA and EJCs may be used around a start codon (-4 to +37 where the A of the AUG codons is +1) in order to decrease the accessibility to the first start codon (AUG). Nucleic acids as agents for delivering anti-CD28 antibodies or binding proteins The compositions of the disclosure can be administered not only as antibodies or antigen-binding fragments, but also in the form of nucleic acids. The exemplary nucleic acids described herein may be used to deliver antibodies or antigen-binding fragments to a subject. These nucleic acids (e.g., RNAs, such as mRNAs) may be used as therapeutic agents to express antibodies or antigen-binding fragments of the disclosure as a therapy to treat a target disease. Pharmaceutical compositions Pharmaceutical compositions containing an antagonistic CD28 antibody or nucleic acid encoding the same can be prepared using methods known in the art. Pharmaceutical compositions described herein may contain an antagonistic CD28 antibody, or a nucleic acid encoding the same, in combination with one or more pharmaceutically acceptable excipients. For instance, pharmaceutical compositions described herein can be prepared using physiologically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (19th ed., 1995), incorporated herein by reference), and in a desired form, e.g., in the form of lyophilized formulations or aqueous solutions. The compositions can also be prepared so as to contain the active agent (e.g., an antagonistic CD28 antibody or a nucleic acid encoding the same) at a desired concentration. For example, a pharmaceutical composition described herein may contain at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%) active agent by weight (w/w). Additionally, an active agent that can be incorporated into a pharmaceutical formulation can itself have a desired level of purity. For example, a polypeptide or nucleic acid described herein may be characterized by a certain degree of purity after isolating the antibody from cell culture media or after chemical synthesis. A polypeptide or nucleic acid described herein may be at least 10% pure prior to incorporating the polypeptide or nucleic acid into a pharmaceutical composition (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or 100% pure). Pharmaceutical compositions can be prepared for storage as lyophilized formulations or aqueous solutions by mixing the active agent having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers typically employed in the art, e.g., buffering agents, stabilizing agents, preservatives, isotonifiers, non-ionic detergents, antioxidants, and other miscellaneous additives. See, e.g., Remington's Pharmaceutical Sciences (19th ed., 1995), incorporated herein by reference). Such additives must be nontoxic to the recipients at the dosages and concentrations employed. Buffering agents Buffering agents help to maintain the pH in the range which approximates physiological conditions. Suitable buffering agents for use with the pharmaceutical compositions of the disclosure include both organic and inorganic acids and salts thereof, such as citrate buffers {e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers {e.g., succinic acid- monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid- disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers {e.g., fumaric acid-monosodium fumarate mixture, fumaric acid- disodium fumarate mixture, monosodium fumarate- disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate buffer (e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.), and acetate buffers {e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). Additionally, phosphate buffers, histidine buffers, and trimethylamine salts such as Tris can be used. Preservatives Preservatives can be added to a composition described herein to inhibit microbial growth. Suitable preservatives for use with the pharmaceutical compositions of the disclosure include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides {e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol. Isotonifiers, also known as “stabilizers,” can be added to ensure isotonicity of liquid compositions described herein and include polhydric sugar alcohols, for example trihydric or higher sugar alcohols, such as glycerin, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the therapeutic agent or helps to prevent denaturation or adherence to the container wall. Typical stabilizers can be polyhydric sugar alcohols; amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol and sodium thio sulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or fewer); proteins such as HSA, BSA, MSA, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone monosaccharides, such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose and trisaccharides such as raffinose; and polysaccharides such as dextran. Detergents In some embodiments, non-ionic surfactants or detergents (also known as “wetting agents”) are added to the pharmaceutical composition to help solubilize the therapeutic agent as well as to protect the therapeutic agent against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stressed without causing denaturation of the protein. Suitable non-ionic surfactants include polysorbates (20, 80, etc.), polyoxamers (184, 188 etc.), Pluronic polyols, polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.). Other pharmaceutical carriers Alternative pharmaceutically acceptable carriers that can be incorporated into a pharmaceutical composition described herein may include dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methyl cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oils, but not limited to. A pharmaceutical composition described herein may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995), which is incorporated herein by reference. Lipid Nanoparticle (LNP) Compositions The present disclosure provides LNP compositions with advantageous properties. The lipid nanoparticle compositions described herein may be used for the delivery of therapeutic and/or prophylactic agents, e.g., mRNAs, to mammalian cells or organs. For example, the lipid nanoparticles described herein have little or no immunogenicity. For example, the lipid compounds disclosed herein have a lower immunogenicity as compared to a reference lipid (e.g., MC3, KC2, or DLinDMA). For example, a formulation comprising a lipid disclosed herein and a therapeutic or prophylactic agent, e.g., mRNA, has an increased therapeutic index as compared to a corresponding formulation which comprises a reference lipid (e.g., MC3, KC2, or DLinDMA) and the same therapeutic or prophylactic agent. In some embodiments, the present application provides pharmaceutical compositions comprising: (a) a delivery agent comprising a lipid nanoparticle; and (b) a polynucleotide encoding an antibody, antigen-binding fragment, or binding protein of the disclosure. a. Lipid Nanoparticles In some embodiments, polynucleotides of the present disclosure (e.g., mRNA) are included in a lipid nanoparticle (LNP). Lipid nanoparticles according to the present disclosure may comprise: (i) an ionizable lipid (e.g., an ionizable amino lipid); (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG- modified lipid. In some embodiments, lipid nanoparticles according to the present disclosure further comprise one or more polynucleotides of the present disclosure (e.g., mRNA). The lipid nanoparticles according to the present disclosure can be generated using components, compositions, and methods as are generally known in the art, see for example PCT/US2016/052352; PCT/US2016/068300; PCT/US2017/037551; PCT/US2015/027400; PCT/US2016/047406; PCT/US2016000129; PCT/US2016/014280; PCT/US2016/014280; PCT/US2017/038426; PCT/US2014/027077; PCT/US2014/055394; PCT/US2016/52117; PCT/US2012/069610; PCT/US2017/027492; PCT/US2016/059575 and PCT/US2016/069491 all of which are incorporated by reference herein in their entirety. In some embodiments, the lipid nanoparticle comprises an ionizable cationic lipid (e.g., an ionizable amino lipid) at a content of 20-60 mol.%, 25-60 mol.%, 30-60 mol.%, 35-60 mol.%, 40-60 mol.%, 45-60 mol.%, 20-55 mol.%, 25-55 mol.%, 30-55 mol.%, 35- 55 mol.%, 40-55 mol.%, 45-55 mol.%, 20-50 mol.%, 25-50 mol.%, 30-50 mol.%, 35-50 mol.%, or 40-50 mol.%. For example, the lipid nanoparticle may comprise an ionizable cationic lipid (e.g., an ionizable amino lipid) at a content of 40-50 mol.%, 45-50 mol.%, 45-46 mol.%, 46-47 mol.%, 47-48 mol.%, 48-49 mol.%, or 49-50 mol.%, for example about 45 mol.%, about 45.5 mol.%, about 46 mol.%, about 46.5 mol.%, about 47 mol.%, about 47.5 mol.%, about 48 mol.%, about 48.5 mol.%, about 49 mol.%, or about 49.5 mol.% ionizable cationic lipid (e.g., an ionizable amino lipid). In some embodiments, the lipid nanoparticle comprises a non-cationic helper lipid or phospholipid at a content of 5-25 mol.%. For example, the lipid nanoparticle may comprise a non-cationic helper lipid or phospholipid at a content of molar ratio of 5- 25 mol.%, 5-20 mol.%, 5-15 mol.%, 10-25 mol.%, 10-20 mol.%, 10-15 mol.%, 5-6 mol.%, 6-7 mol.%, 7-8 mol.%, 8-9 mol.%, 9-10 mol.%, 10-11 mol.%, 11-12 mol.%, 12- 13 mol.%, 13-14 mol.%, 14-15 mol.%, 10-14 mol.%, 10-13 mol.%, 10-12 mol.%, 10-11 mol.%, 9-15 mol.%, 9-14 mol.%, 9-13 mol.%, 9-12 mol.%, or 9-11 mol.% non-cationic lipid. In some embodiments, the lipid nanoparticle comprises a sterol or other structural lipid at a content molar ratio of 25-55 mol.%, 25-50 mol.%, 25-45 mol.%, 25- 40 mol.%, 25-35 mol.%, 30-55 mol.%, 30-50 mol.%, 30-45 mol.%, 30-40 mol.%, 30-35 mol.%, 35-55 mol.%, 35-50 mol.%, 35-45 mol.%, 35-40 mol.%, 25-30 mol.%, 30-35 mol.%, 25-28 mol.%, 28-30 mol.%, 30-33 mol.%, 35-38 mol.%, 38-40 mol.%, 36-40 mol.%, 37-40 mol.%, 38-40 mol.%, 38-39 mol.%, 36-40 mol.%, 37-40 mol.%, 36-39 mol.%, or 37-39 mol.%. For example, the lipid nanoparticle may comprise a sterol or other structural lipid at a content of about 30 mol.%, about 30.5 mol.%, about 31.0 mol.%, about 31.5 mol.%, about 32.0 mol.%, about 32.5 mol.%, about 33.0 mol.%, about 33.5 mol.%, about 34.0 mol.%, about 34.5 mol.%, about 35.0 mol.%, about 35.5 mol.%, about 36.0 mol.%, about 36.5 mol.%, about 37.0 mol.%, about 37.5 mol.%, about 38.0 mol.%, about 38.5 mol.%, about 39.0 mol.%, about 39.5 mol.%, about 40.0 mol.%, about 40.5 mol.%, about 41.0 mol.%, about 41.5 mol.%, about 42.0 mol.%, about 42.5 mol.%, about 43.0 mol.%, about 43.5 mol.%, about 44.0 mol.%, about 44.5 mol.%, or about 45.0 mol.%. In some embodiments, the lipid nanoparticle comprises a PEG-modified lipid at a content of 0.5-15 mol.%, 1.0-15 mol.%, 1.5-15 mol.%, 2.0-15 mol.%, 2.5-15 mol.%, 3.0- 15 mol.%, 3.5-15 mol.%, 4.0-15 mol.%, 4.5-15 mol.%, 5.0-15 mol.%, 10-15 mol.%, 0.5- 10 mol.%, 0.5-5 mol.%, 0.5-4.5 mol.%, 0.5-4.0 mol.%, 0.5-3.5 mol.%, 0.5-3.0 mol.%, 0.5-2.5 mol.%, 0.5-2.0 mol.%, 0.5-1.5 mol.%, 0.5-1.0 mol.%, 1.0-10 mol.%, 1.0-5 mol.%, 1.0-4.5 mol.%, 1.0-4.0 mol.%, 1.0-3.5 mol.%, 1.0-3.0 mol.%, 1.0-2.5 mol.%, 1.0-2.0 mol.%, 1.0-1.5 mol.%, 1.5-5.0 mol.%, 1.5-4.5 mol.%, 1.5-4.0 mol.%, 1.5-3.5 mol.%, 1.5- 3.0 mol.%, 1.5-2.5 mol.%, 1.5-2.0 mol.%, 2.0-5.0 mol.%, 2.0-4.5 mol.%, 2.0-4.0 mol.%, 2.0-3.5 mol.%, 2.0-3.0 mol.%, or 2.0-2.5 mol.%. For example, the lipid nanoparticle may comprise a PEG-modified lipid at a content of a about 0.5 mol.%, about 1.0 mol.%, about 1.5 mol.%, about 2.0 mol.%, about 2.5 mol.%, about 3.0 mol.%, about 3.5 mol.%, about 4.0 mol.%, about 4.5 mol.%, about 5.0 mol.%, about 6.0 mol.%, about 7.0 mol.%, about 8.0 mol.%, about 9.0 mol.%, about 10.0 mol.%, or about 15.0 mol.%. In some embodiments, the lipid nanoparticle comprises: (i) 20 to 60 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 25 to 55 mol.% sterol or other structural lipid, (iii) 5 to 25 mol.% non-cationic lipid (e.g., phospholipid), and (iv) 0.5 to 15 mol.% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises: (i) 40 to 50 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 30 to 45 mol.% sterol or other structural lipid, (iii) 5 to 15 mol.% non-cationic lipid (e.g., phospholipid), and (iv) 1 to 5 mol.% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises: (i) 45 to 50 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 35 to 45 mol.% sterol or other structural lipid, (iii) 8 to 12 mol.% non-cationic lipid (e.g., phospholipid), and (iv) 1.5 to 3.5 mol.% PEG-modified lipid. In the following sections, “Compounds” numbered with an “I-” prefix (e.g., “Compound I-1,” “Compound I-2,” “Compound I-3,” “Compound I-VI,” etc., indicate specific ionizable lipid compounds. Likewise, compounds numbered with a “P-” prefix (e.g., “Compound P-I,” etc.) indicate a specific PEG-modified lipid compound. b. Ionizable amino lipids In some embodiments, the lipid nanoparticle of the present disclosure comprises an ionizable cationic lipid (e.g., an ionizable amino lipid) that is a compound of Formula (I):

; wherein

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, in Formula (I), R’^a is R’^branched; R’^branched is

;

denotes a point of attachment; R^aα, R^aβ, R^aγ, and R^aδ are each H; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each - C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments, in Formula (I), R’^a is R’^branched; R’^branched is denotes a p ^{aα aβ aγ aδ}

oint of attachment; R , R , R , and R are each H; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 3; and m is 7. In some embodiments of the compounds of Formula (I), R’^a is R’^branched; R’^branched is denotes a point of atta ^aα

chment; R is C_2-12 alkyl; R^aβ, R^aγ, and R^aδ are each H; R² and R³ are each C_1-14 alkyl; R⁴ is

; R¹⁰ is NH(C_1-6 alkyl); n2 is 2; R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments of the compounds of Formula (I), R’^a is R’^branched; R’^branched is d ^{aα aβ}

enotes a point of attachment; R , R , and R^aδ are each H; R^aγ is C_2-12 alkyl; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments, the compound of Formula (I) is selected from:

In some embodiments, the compound of Formula (I) is:

(Compound I-1). In some embodiments, the compound of Formula (I) is:

In some embodiments, the compound of Formula (I) is:

In some aspects, the disclosure relates to a compound of Formula (Ia):

(Ia) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched; wherein R’^branched is:

; wherein

denotes a point of attachment; wherein R^aβ, R^aγ, and R^aδ are each independently selected from the group consisting of H, C_2-12 alkyl, and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some aspects, the disclosure relates to a compound of Formula (Ib):

(Ib) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched; wherein R’^branched is:

; wherein

denotes a point of attachment; wherein R^aα, R^aβ, R^aγ, and R^aδ are each independently selected from the group consisting of H, C_2-12 alkyl, and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is -(CH₂)_nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments of Formula (I) or (Ib), R’^a is R’^branched; R’^branched is denotes a point of attachment; R^aβ, R^aγ, an ^{aδ 2}

d R are each H; R and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments of Formula (I) or (Ib), R’^a is R’^branched; R’^branched is denotes a poin ^{aβ aδ aγ}

t of attachment; R and R are each H; R is C_2- 12 alkyl; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments, the disclosure relates to a compound of Formula (Ic):

(Ic) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched; wherein R’^branched is:

; wherein

denotes a point of attachment; wherein R^aα, R^aβ, R^aγ, and R^aδ are each independently selected from the group consisting of H, C_2-12 alkyl, and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13. In some embodiments, R’^a is R’^branched; R’^branched is

denotes a point of attachment; R^aβ, R^aγ, and R^aδ are each H; R^aα is C_2-12 alkyl; R² and R³ are each C_1-14 alkyl; R⁴ is

; denotes a point of attachment; R¹⁰ is NH(C_1-6 alkyl); n2 is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7. In some embodiments, the compound of Formula (Ic) is:

(Compound I-2). In some aspects, the disclosure relates to a compound of Formula (II):

(II) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is:

and R’^cyclic is:

; and R’^b is: ;

wherein

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; Y^a is a C_3-6 carbocycle; R*”^a is selected from the group consisting of C_1-15 alkyl and C_2-15 alkenyl; and s is 2 or 3; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-a): (II-a) or its N-oxide, or a salt or isomer thereof,

wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: ^b

and R’ is:

wherein

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-b):

(II-b) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is:

and R’^b is:

wherein

denotes a point of attachment; R^aγ and R^bγ are each independently selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-c):

and R’ is:

; wherein

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R’ is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-d):

(II-d) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: and R’^b

is:

wherein

denotes a point of attachment; wherein R^aγ and R^bγ are each independently selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R’ independently is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some aspects, the disclosure relates to a compound of Formula (II-e):

(II-e) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is: and ^b

R’ is:

; wherein

denotes a point of attachment; wherein R^aγ is selected from the group consisting of C_1-12 alkyl and C_2-12 alkenyl; R² and R³ are each independently selected from the group consisting of C_1-14 alkyl and C_2-14 alkenyl; R⁴ is -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; R’ is a C_1-12 alkyl or C_2-12 alkenyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each independently selected from 4, 5, and 6. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each 5. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), each R’ independently is a C_1-12 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), each R’ independently is a C_2-5 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^b is:

and R² and R³ are each independently a C_1-14 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^b is:

and R² and R³ are each independently a C_6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^b is: ²

and R and R³ are each a C₈ alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: ^{b aγ 2}

and R’ is:

, R is a C_1-12 alkyl and R and R³ are each independently a C_6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: and R’^b is:

, R^aγ is a C_2-6 alkyl and R² and R³ are each independently a C_6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: ^{b aγ 2 3}

and R’ is:

, R is a C_2-6 alkyl, and R and R are each a C₈ alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is:

, R’^b is:

, and R^aγ and R^bγ are each a C_1-12 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is

, R’^b is:

, and R^aγ and R^bγ are each a C_2-6 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each independently selected from 4, 5, and 6 and each R’ independently is a C_1-12 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), m and l are each 5 and each R’ independently is a C_2-5 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is:

, R’^b is:

, m and l are each independently selected from 4, 5, and 6, each R’ independently is a C_1-12 alkyl, and R^aγ and R^bγ are each a C_1-12 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: ^b

, R’ is: ,

m and l are each 5, each R’ independently is a C_2-5 alkyl, and R^aγ and R^bγ are each a C_2- ₆ alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: and R’^b is:

, m and l are each

independently selected from 4, 5, and 6, R’ is a C_1-12 alkyl, R^aγ is a C_1-12 alkyl and R² and R³ are each independently a C_6-10 alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: ^b

and R’ is:

, m and l are each 5, R’ is a C_2-5 alkyl, R^aγ is a C_2-6 alkyl, and R² and R³ are each a C₈ alkyl. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R⁴ is

, wherein R¹⁰ is NH(C_1-6 alkyl) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R⁴ is

, wherein R¹⁰ is NH(CH₃) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is:

, R’^b is:

, m and l are each independently selected from 4, 5, and 6, each R’ independently is a C_1-12 alkyl, R^aγ and R^bγ are each a C_1-12 alkyl, and R⁴ is

, wherein R¹⁰ is NH(C_1-6 alkyl), and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: ^b

, R’ is:

, m and l are each 5, each R’ independently is a C_2-5 alkyl, R^aγ and R^bγ are each a C_2-6 alkyl, and R⁴ is

and R’^b is:

, m and l are each independently selected from 4, 5, and 6, R’ is a C_1-12 alkyl, R² and R³ are each independently a C_6-10 alkyl, R^aγ is a C_1-12 alkyl, and R⁴ is

, wherein R¹⁰ is NH(C_1-6 alkyl) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: and R’^b is:

m and l are each 5, R’ is a C_2-5 alkyl, R^aγ is a C_2-6 alkyl, R² and R³ are each a C₈ alkyl, and R⁴ is

, wherein R¹⁰ is NH(CH₃) and n2 is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R⁴ is -(CH₂)_nOH and n is 2, 3, or 4. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R⁴ is -(CH₂)_nOH and n is 2. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is: , R^b

’ is:

, m and l are each independently selected from 4, 5, and 6, each R’ independently is a C_1-12 alkyl, R^aγ and R^bγ are each a C_1-12 alkyl, R⁴ is -(CH₂)_nOH, and n is 2, 3, or 4. In some embodiments of the compound of Formula (II), (II-a), (II-b), (II-c), (II-d), or (II-e), R’^branched is:

, R’^b is:

, m and l are each 5, each R’ independently is a C_2-5 alkyl, R^aγ and R^bγ are each a C_2-6 alkyl, R⁴ is -(CH₂)_nOH, and n is 2. In some aspects, the disclosure relates to a compound of Formula (II-f):

(II-f) or its N-oxide, or a salt or isomer thereof, wherein R’^a is R’^branched or R’^cyclic; wherein R’^branched is:

and R’^b is:

; wherein

denotes a point of attachment; R^aγ is a C_1-12 alkyl; R² and R³ are each independently a C_1-14 alkyl; R⁴ is -(CH₂)_nOH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5; R’ is a C_1-12 alkyl; m is selected from 4, 5, and 6; and l is selected from 4, 5, and 6. In some embodiments of the compound of Formula (II-f), m and l are each 5, and n is 2, 3, or 4. In some embodiments of the compound of Formula (II-f) R’ is a C_2-5 alkyl, R^aγ is a C_2-6 alkyl, and R² and R³ are each a C_6-10 alkyl. In some embodiments of the compound of Formula (II-f), m and l are each 5, n is 2, 3, or 4, R’ is a C_2-5 alkyl, R^aγ is a C_2-6 alkyl, and R² and R³ are each a C_6-10 alkyl. In some aspects, the disclosure relates to a compound of Formula (II-g):

(II-g), wherein R^aγ is a C_2-6 alkyl; R’ is a C_2-5 alkyl; and R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 3, 4, and 5, and

, wherein

denotes a point of attachment, R¹⁰ is NH(C_1-6 alkyl), and n2 is selected from the group consisting of 1, 2, and 3. In some aspects, the disclosure relates to a compound of Formula (II-h):

(II-h), wherein R^aγ and R^bγ are each independently a C_2-6 alkyl; each R’ independently is a C_2-5 alkyl; and R⁴ is selected from the group consisting of -(CH₂)_nOH wherein n is selected from the group consisting of 3, 4, and 5, and

, wherein

denotes a point of attachment, R¹⁰ is NH(C_1-6 alkyl), and n2 is selected from the group consisting of 1, 2, and 3. In some embodiments of the compound of Formula (II-g) or (II-h), R⁴ is

, wherein R¹⁰ is NH(CH₃) and n2 is 2. In some embodiments of the compound of Formula (II-g) or (II-h), R⁴ is - (CH₂)₂OH. In some aspects, the disclosure relates to a compound having the Formula (III):

(III), or a salt or isomer thereof, wherein R₁, R₂, R₃, R₄, and R5 are independently selected from the group consisting of C_5-20 alkyl, C_5-20 alkenyl, -R”MR’, -R*YR”, -YR”, and -R*OR”; each M is independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC( S)-, -CH(OH)-, -P(O)(OR’)O-, -S(O)₂-, an aryl group, and a heteroaryl group; X¹, X², and X³ are independently selected from the group consisting of a bond, -CH₂-, -(CH₂)₂-, -CHR-, -CHY-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)-CH₂-, -CH₂-C(O)-, -C(O)O-CH₂-, -OC(O)-CH₂-, -CH₂-C(O)O-, -CH₂-OC(O)-, -CH(OH)-, -C(S)-, and -CH(SH)-; each Y is independently a C_3-6 carbocycle; each R* is independently selected from the group consisting of C_1-12 alkyl and C_2- ₁₂ alkenyl; each R is independently selected from the group consisting of C_1-3 alkyl and a C_3- ₆ carbocycle; each R’ is independently selected from the group consisting of C_1-12 alkyl, C_2-12 alkenyl, and H; and each R” is independently selected from the group consisting of C3-12 alkyl and C_3- ₁₂ alkenyl, and wherein: i) at least one of X¹, X², and X³ is not -CH₂-; and/or ii) at least one of R₁, R₂, R₃, R₄, and R₅ is -R”MR’. In some embodiments, R₁, R₂, R₃, R₄, and R₅ are each C_5-20 alkyl; X¹ is -CH₂-; and X² and X³ are each -C(O)-. In some embodiments, the compound of Formula (III) is:

(Compound I-VI), or a salt or isomer thereof. c. Phospholipids The lipid composition of the lipid nanoparticle composition disclosed herein can comprise one or more phospholipids, for example, one or more saturated or (poly)unsaturated phospholipids or a combination thereof. In general, phospholipids comprise a phospholipid moiety and one or more fatty acid moieties. A phospholipid moiety can be selected, for example, from the non-limiting group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and a sphingomyelin. A fatty acid moiety can be selected, for example, from the non-limiting group consisting of lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanoic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Particular phospholipids can facilitate fusion to a membrane. For example, a cationic phospholipid can interact with one or more negatively charged phospholipids of a membrane (e.g., a cellular or intracellular membrane). Fusion of a phospholipid to a membrane can allow one or more elements (e.g., a therapeutic agent) of a lipid- containing composition (e.g., LNPs) to pass through the membrane permitting, e.g., delivery of the one or more elements to a target tissue. Non-natural phospholipid species including natural species with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated. For example, a phospholipid can be functionalized with or cross-linked to one or more alkynes (e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond). Under appropriate reaction conditions, an alkyne group can undergo a copper-catalyzed cycloaddition upon exposure to an azide. Such reactions can be useful in functionalizing a lipid bilayer of a nanoparticle composition to facilitate membrane permeation or cellular recognition or in conjugating a nanoparticle composition to a useful component such as a targeting or imaging moiety (e.g., a dye). Phospholipids include, but are not limited to, glycerophospholipids such as phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, phosphatidy glycerols, and phosphatidic acids. Phospholipids also include phosphosphingolipid, such as sphingomyelin. In some embodiments, a phospholipid of the present disclosure comprises 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-gly cero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2 cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine,1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoyl- sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2- dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is an analog or variant of DSPC. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is a compound of Formula (IV):

(IV), or a salt thereof, wherein: each R¹ is independently optionally substituted alkyl; or optionally two R¹ are joined together with the intervening atoms to form optionally substituted monocyclic carbocyclyl or optionally substituted monocyclic heterocyclyl; or optionally three R¹ are joined together with the intervening atoms to form optionally substituted bicyclic carbocyclyl or optionally substitute bicyclic heterocyclyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the Formula:

each instance of L² is independently a bond or optionally substituted C_1-6 alkylene, wherein one methylene unit of the optionally substituted C_1-6 alkylene is optionally replaced with O, N(R^N), S, C(O), C(O)N(R^N), NR^NC(O), C(O)O, OC(O), - OC(O)O, OC(O)N(R^N), NR^NC(O)O, or NR^NC(O)N(R^N); each instance of R² is independently optionally substituted C_1-30 alkyl, optionally substituted C_1-30 alkenyl, or optionally substituted C_1-30 alkynyl; optionally wherein one or more methylene units of R² are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(R^N), O, S, C(O), C(O)N(R^N), NR^NC(O), - NR^NC(O)N(R^N), C(O)O, OC(O), OC(O)O, OC(O)N(R^N), NR^NC(O)O, C(O)S, SC(O), - C(=NR^N), C(=NR^N)N(R^N), NR^NC(=NR^N), NR^NC(=NR^N)N(R^N), C(S), C(S)N(R^N), NR^NC(S), NR^NC(S)N(R^N), S(O), OS(O), S(O)O, OS(O)O, OS(O)₂, S(O)₂O, OS(O)₂O, N(R^N)S(O), S(O)N(R^N), N(R^N)S(O)N(R^N), OS(O)N(R^N), N(R^N)S(O)O, S(O)₂, N(R^N)S(O)₂, - S(O)₂N(R^N), N(R^N)S(O)₂N(R^N), OS(O)₂N(R^N), or N(R^N)S(O)₂O; each instance of R^N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2; provided that the compound is not of the Formula:

, wherein each instance of R² is independently unsubstituted alkyl, unsubstituted alkenyl, or unsubstituted alkynyl. In some embodiments, the phospholipids may be one or more of the phospholipids described in U.S. Application No.62/520,530. i. Phospholipid Head Modifications In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phospholipid head (e.g., a modified choline group). In certain embodiments, a phospholipid with a modified head is DSPC, or analog thereof, with a modified quaternary amine. For example, in embodiments of Formula (IV), at least one of R¹ is not methyl. In certain embodiments, at least one of R¹ is not hydrogen or methyl. In certain embodiments, the compound of Formula (IV) is of one of the following Formulae:

or a salt thereof, wherein: each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each u is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each v is independently 1, 2, or 3. In certain embodiments, a compound of Formula (IV) is of Formula (IV-a):

(IV-a), or a salt thereof. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a cyclic moiety in place of the glyceride moiety. In certain embodiments, a phospholipid useful in the present disclosure is DSPC, or analog thereof, with a cyclic moiety in place of the glyceride moiety. In certain embodiments, the compound of Formula (IV) is of Formula (IV-b): ,

or a salt thereof. ii. Phospholipid Tail Modifications In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified tail. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is DSPC, or analog thereof, with a modified tail. As described herein, a “modified tail” may be a tail with shorter or longer aliphatic chains, aliphatic chains with branching introduced, aliphatic chains with substituents introduced, aliphatic chains wherein one or more methylenes are replaced by cyclic or heteroatom groups, or any combination thereof. For example, in certain embodiments, the compound of (IV) is of Formula (IV-a), or a salt thereof, wherein at least one instance of R² is each instance of R² is optionally substituted C_1-30 alkyl, wherein one or more methylene units of R² are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(R^N), O, S, C(O), C(O)N(R^N), NR^NC(O), - NR^NC(O)N(R^N), C(O)O, OC(O), OC(O)O, OC(O)N(R^N), NR^NC(O)O, C(O)S, SC(O), - C(=NR^N), C(=NR^N)N(R^N), NR^NC(=NR^N), NR^NC(=NR^N)N(R^N), C(S), C(S)N(R^N), NR^NC(S), NR^NC(S)N(R^N), S(O), OS(O), S(O)O, OS(O)O, OS(O)₂, S(O)₂O, OS(O)₂O, N(R^N)S(O), S(O)N(R^N), N(R^N)S(O)N(R^N), OS(O)N(R^N), N(R^N)S(O)O, S(O)₂, N(R^N)S(O)₂, - S(O)₂N(R^N), N(R^N)S(O)₂N(R^N), OS(O)₂N(R^N), or N(R^N)S(O)₂O. In certain embodiments, the compound of Formula (IV) is of Formula (IV-c):

or a salt thereof, wherein: each x is independently an integer between 0-30, inclusive; and each instance is G is independently selected from the group consisting of optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(R^N), O, S, C(O), C(O)N(R^N), NR^NC(O), NR^NC(O)N(R^N), C(O)O, OC(O), OC(O)O, OC(O)N(R^N), NR^NC(O)O, C(O)S, SC(O), C(=NR^N), C(=NR^N)N(R^N), NR^NC(=NR^N), NR^NC(=NR^N)N(R^N), C(S), C(S)N(R^N), NR^NC(S), NR^NC(S)N(R^N), S(O), OS(O), S(O)O, OS(O)O, OS(O)₂, S(O)₂O, OS(O)₂O, - N(R^N)S(O), S(O)N(R^N), N(R^N)S(O)N(R^N), OS(O)N(R^N), N(R^N)S(O)O, S(O)₂, N(R^N)S(O)₂, S(O)₂N(R^N), N(R^N)S(O)₂N(R^N), OS(O)₂N(R^N), or N(R^N)S(O)₂O. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid useful or potentially useful in the present disclosure is a compound of Formula (IV), wherein n is 1, 3, 4, 5, 6, 7, 8, 9, or 10. For example, in certain embodiments, a compound of Formula (IV) is of one of the following Formulae:

, , or a salt thereof. iii. Alternative Lipids In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid useful. In certain embodiments, an alternative lipid is used in place of a phospholipid of the present disclosure. In certain embodiments, an alternative lipid of the present disclosure is oleic acid. In certain embodiments, the alternative lipid is one of the following: , ,

,

. d. Structural Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more structural lipids. As used herein, the term "structural lipid" refers to sterols and also to lipids containing sterol moieties. Incorporation of structural lipids in the lipid nanoparticle may help mitigate aggregation of other lipids in the particle. Structural lipids can be selected from the group including but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha- tocopherol, hopanoids, phytosterols, steroids, and mixtures thereof. In some embodiments, the structural lipid is a sterol. As defined herein, "sterols" are a subgroup of steroids consisting of steroid alcohols. In certain embodiments, the structural lipid is a steroid. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid is an analog of cholesterol. In certain embodiments, the structural lipid is alpha-tocopherol. In some embodiments, the structural lipids may be one or more of the structural lipids described in U.S. Application No.62/520,530. e. Polyetylene Glycol (PEG)-Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more a polyethylene glycol (PEG) lipid. As used herein, the term “PEG-lipid” refers to polyethylene glycol (PEG)-modified lipids. Non-limiting examples of PEG-lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines and PEG-modified 1,2- diacyloxypropan-3-amines. Such lipids are also referred to as PEGylated lipids. For example, a PEG lipid can be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments, the PEG-lipid includes, but not limited to 1,2-dimyristoyl- sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG- diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), or PEG-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA). In some embodiments, the PEG-lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG- modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. In some embodiments, the lipid moiety of the PEG-lipids includes those having lengths of from about C₁₄ to about C₂₂, preferably from about C₁₄ to about C₁₆. In some embodiments, a PEG moiety, for example an mPEG-NH₂, has a size of about 1000, 2000, 5000, 10,000, 15,000 or 20,000 daltons. In some embodiments, the PEG-lipid is PEG_2k-DMG. In some embodiments, the lipid nanoparticles described herein can comprise a PEG lipid which is a non-diffusible PEG. Non-limiting examples of non-diffusible PEGs include PEG-DSG and PEG-DSPE. PEG-lipids are known in the art, such as those described in U.S. Patent No. 8,158,601 and International Publ. No. WO 2015/130584 A2, which are incorporated herein by reference in their entirety. In general, some of the other lipid components (e.g., PEG lipids) of various Formulae, described herein may be synthesized as described International Patent Application No. PCT/US2016/000129, filed December 10, 2016, entitled “Compositions and Methods for Delivery of Therapeutic Agents,” which is incorporated by reference in its entirety. The lipid component of a lipid nanoparticle composition may include one or more molecules comprising polyethylene glycol, such as PEG or PEG-modified lipids. Such species may be alternately referred to as PEGylated lipids. A PEG lipid is a lipid modified with polyethylene glycol. A PEG lipid may be selected from the non-limiting group including PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments the PEG-modified lipids are a modified form of PEG DMG. PEG-DMG has the following structure:

In some embodiments, PEG lipids useful in the present disclosure can be PEGylated lipids described in International Publication No. WO2012099755, the contents of which is herein incorporated by reference in its entirety. Any of these exemplary PEG lipids described herein may be modified to comprise a hydroxyl group on the PEG chain. In certain embodiments, the PEG lipid is a PEG-OH lipid. As generally defined herein, a “PEG-OH lipid” (also referred to herein as “hydroxy- PEGylated lipid”) is a PEGylated lipid having one or more hydroxyl (–OH) groups on the lipid. In certain embodiments, the PEG-OH lipid includes one or more hydroxyl groups on the PEG chain. In certain embodiments, a PEG-OH or hydroxy-PEGylated lipid comprises an –OH group at the terminus of the PEG chain. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, a PEG lipid useful in the present disclosure is a compound of Formula (V). Provided herein are compounds of Formula (V):

(V), or salts thereof, wherein: R³ is –OR^O; R^O is hydrogen, optionally substituted alkyl, or an oxygen protecting group; r is an integer between 1 and 100, inclusive; L¹ is optionally substituted C_1-10 alkylene, wherein at least one methylene of the optionally substituted C_1-10 alkylene is independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, O, N(R^N), S, C(O), C(O)N(R^N), NR^NC(O), C(O)O, OC(O), OC(O)O, OC(O)N(R^N), NR^NC(O)O, or NR^NC(O)N(R^N); D is a moiety obtained by click chemistry or a moiety cleavable under physiological conditions; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the Formula:

each instance of L² is independently a bond or optionally substituted C_1-6 alkylene, wherein one methylene unit of the optionally substituted C_1-6 alkylene is optionally replaced with O, N(R^N), S, C(O), C(O)N(R^N), NR^NC(O), C(O)O, OC(O), - OC(O)O, OC(O)N(R^N), NR^NC(O)O, or NR^NC(O)N(R^N); each instance of R² is independently optionally substituted C_1-30 alkyl, optionally substituted C_1-30 alkenyl, or optionally substituted C_1-30 alkynyl; optionally wherein one or more methylene units of R² are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(R^N), O, S, C(O), C(O)N(R^N), NR^NC(O), - NR^NC(O)N(R^N), C(O)O, OC(O), OC(O)O, OC(O)N(R^N), NR^NC(O)O, C(O)S, SC(O), - C(=NR^N), C(=NR^N)N(R^N), NR^NC(=NR^N), NR^NC(=NR^N)N(R^N), C(S), C(S)N(R^N), NR^NC(S), NR^NC(S)N(R^N), S(O) , OS(O), S(O)O, OS(O)O, OS(O)₂, S(O)₂O, OS(O)₂O, N(R^N)S(O), S(O)N(R^N), N(R^N)S(O)N(R^N), OS(O)N(R^N), N(R^N)S(O)O, S(O)₂, N(R^N)S(O)₂, - S(O)₂N(R^N), N(R^N)S(O)₂N(R^N), OS(O)₂N(R^N), or N(R^N)S(O)₂O; each instance of R^N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2. In certain embodiments, the compound of Fomula (V) is a PEG-OH lipid (i.e., R³ is –OR^O, and R^O is hydrogen). In certain embodiments, the compound of Formula (V) is of Formula (V-OH):

(V-OH), or a salt thereof. In certain embodiments, a PEG lipid useful in the present disclosure is a PEGylated fatty acid. In certain embodiments, a PEG lipid useful in the present disclosure is a compound of Formula (VI). Provided herein are compounds of Formula (VI):

or a salts thereof, wherein: R³ is–OR^O; R^O is hydrogen, optionally substituted alkyl or an oxygen protecting group; r is an integer between 1 and 100, inclusive; R⁵ is optionally substituted C_10-40 alkyl, optionally substituted C_10-40 alkenyl, or optionally substituted C10-40 alkynyl; and optionally one or more methylene groups of R⁵ are replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, - N(R^N), O, S, C(O), C(O)N(R^N), NR^NC(O), NR^NC(O)N(R^N), C(O)O, OC(O), OC(O)O, - OC(O)N(R^N), NR^NC(O)O, C(O)S, SC(O), C(=NR^N), C(=NR^N)N(R^N), NR^NC(=NR^N), - NR^NC(=NR^N)N(R^N), C(S), C(S)N(R^N), NR^NC(S), NR^NC(S)N(R^N), S(O), OS(O), S(O)O, OS(O)O, OS(O)₂, S(O)₂O, OS(O)₂O, N(R^N)S(O), S(O)N(R^N), N(R^N)S(O)N(R^N), - OS(O)N(R^N), N(R^N)S(O)O, S(O)₂, N(R^N)S(O)₂, S(O)₂N(R^N), N(R^N)S(O)₂N(R^N), - OS(O)₂N(R^N), or N(R^N)S(O)₂O; and each instance of R^N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, the compound of Formula (VI) is of Formula (VI-OH):

(VI-OH), or a salt thereof. In some embodiments, r is 45. In yet other embodiments the compound of Formula (VI) is:

or a salt thereof. In one embodiment, r is 40-50. In some embodiments, the compound of Formula (VI) is

(Compound P-I). In some aspects, the lipid composition of the pharmaceutical compositions disclosed herein does not comprise a PEG-lipid. In some embodiments, the PEG-lipids may be one or more of the PEG lipids described in U.S. Application No.62/520,530. In some embodiments, a PEG lipid of the present disclosure comprises a PEG- modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG- modified dialkylglycerol, and mixtures thereof. In some embodiments, the PEG- modified lipid is PEG-DMG, PEG-c-DOMG (also referred to as PEG-DOMG), PEG-DSG and/or PEG-DPG. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of any of Formula I, II or III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising PEG-DMG. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of any of Formula I, II or III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid comprising a compound having Formula IV, a structural lipid, and the PEG lipid comprising a compound having Formula V or VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid comprising a compound having Formula IV, a structural lipid, and the PEG lipid comprising a compound having Formula V or VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula I, II or III, a phospholipid having Formula IV, a structural lipid, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of

, and a PEG lipid comprising Formula VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of

, and an alternative lipid comprising oleic acid. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of

, an alternative lipid comprising oleic acid, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of

a phospholipid comprising DOPE, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of

, a phospholipid comprising DOPE, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula VI. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of from about 2:1 to about 30:1. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of about 6:1. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of about 3:1. In some embodiments, a LNP of the present disclosure comprises a wt/wt ratio of the ionizable cationic lipid component to the RNA of from about 10:1 to about 100:1. In some embodiments, a LNP of the present disclosure comprises a wt/wt ratio of the ionizable cationic lipid component to the RNA of about 20:1. In some embodiments, a LNP of the present disclosure comprises a wt/wt ratio of the ionizable cationic lipid component to the RNA of about 10:1. In some embodiments, a LNP of the present disclosure has a mean diameter from about 50nm to about 150nm. In some embodiments, a LNP of the present disclosure has a mean diameter from about 70nm to about 120nm. Other Lipid Composition Components The lipid composition of a pharmaceutical composition disclosed herein can include one or more components in addition to those described above. For example, the lipid composition can include one or more permeability enhancer molecules, carbohydrates, polymers, surface altering agents (e.g., surfactants), or other components. For example, a permeability enhancer molecule can be a molecule described by U.S. Patent Application Publication No.2005/0222064. Carbohydrates can include simple sugars (e.g., glucose) and polysaccharides (e.g., glycogen and derivatives and analogs thereof). A polymer can be included in and/or used to encapsulate or partially encapsulate a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition in lipid nanoparticle form). A polymer can be biodegradable and/or biocompatible. A polymer can be selected from, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, polystyrenes, polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyleneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. The ratio between the lipid composition and the polynucleotide range can be from about 10:1 to about 60:1 (wt/wt). In some embodiments, the ratio between the lipid composition and the polynucleotide can be about 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1 or 60:1 (wt/wt). In some embodiments, the wt/wt ratio of the lipid composition to the polynucleotide encoding a therapeutic agent is about 20:1 or about 15:1. In some embodiments, the pharmaceutical composition disclosed herein can contain more than one polypeptides. For example, a pharmaceutical composition disclosed herein can contain two or more polynucleotides (e.g., RNA, e.g., mRNA). In some embodiments, the lipid nanoparticles described herein can comprise polynucleotides (e.g., mRNA) in a lipid:polynucleotide weight ratio of 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1 or 70:1, or a range or any of these ratios such as, but not limited to, 5:1 to about 10:1, from about 5:1 to about 15:1, from about 5:1 to about 20:1, from about 5:1 to about 25:1, from about 5:1 to about 30:1, from about 5:1 to about 35:1, from about 5:1 to about 40:1, from about 5:1 to about 45:1, from about 5:1 to about 50:1, from about 5:1 to about 55:1, from about 5:1 to about 60:1, from about 5:1 to about 70:1, from about 10:1 to about 15:1, from about 10:1 to about 20:1, from about 10:1 to about 25:1, from about 10:1 to about 30:1, from about 10:1 to about 35:1, from about 10:1 to about 40:1, from about 10:1 to about 45:1, from about 10:1 to about 50:1, from about 10:1 to about 55:1, from about 10:1 to about 60:1, from about 10:1 to about 70:1, from about 15:1 to about 20:1, from about 15:1 to about 25:1,from about 15:1 to about 30:1, from about 15:1 to about 35:1, from about 15:1 to about 40:1, from about 15:1 to about 45:1, from about 15:1 to about 50:1, from about 15:1 to about 55:1, from about 15:1 to about 60:1 or from about 15:1 to about 70:1. In some embodiments, the lipid nanoparticles described herein can comprise the polynucleotide in a concentration from approximately 0.1 mg/ml to 2 mg/ml such as, but not limited to, 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1.0 mg/ml, 1.1 mg/ml, 1.2 mg/ml, 1.3 mg/ml, 1.4 mg/ml, 1.5 mg/ml, 1.6 mg/ml, 1.7 mg/ml, 1.8 mg/ml, 1.9 mg/ml, 2.0 mg/ml or greater than 2.0 mg/ml. a. Nanoparticle Compositions In some embodiments, the pharmaceutical compositions disclosed herein are Formulated as lipid nanoparticles (LNP). Accordingly, the present disclosure also provides nanoparticle compositions comprising (i) a lipid composition comprising a delivery agent such as compound as described herein, and (ii) a polynucleotide encoding a polypeptide. In such nanoparticle composition, the lipid composition disclosed herein can encapsulate the polynucleotide encoding a polypeptide. Nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less. Nanoparticle compositions include, for example, lipid nanoparticles (LNPs), liposomes, and lipoplexes. In some embodiments, nanoparticle compositions are vesicles including one or more lipid bilayers. In certain embodiments, a nanoparticle composition includes two or more concentric bilayers separated by aqueous compartments. Lipid bilayers can be functionalized and/or crosslinked to one another. Lipid bilayers can include one or more ligands, proteins, or channels. In some embodiments, a lipid nanoparticle comprises an ionizable amino lipid, a structural lipid, a phospholipid, and mRNA. In some embodiments, the LNP comprises an ionizable amino lipid, a PEG-modified lipid, a sterol and a structural lipid. In some embodiments, the LNP has a molar ratio of about 40-50% ionizable amino lipid; about 5-15% structural lipid; about 30-45% sterol; and about 1-5% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises 47-49 mol.% ionizable cationic lipid (e.g. ionizable amino lipid, e.g., Compound I-1, Compound I-2, or Compound I-3), 10-12 mol.% non-cationic lipid (e.g., phospholipid, e.g., DSPC), 38-40 mol.% sterol (e.g., cholesterol) or other structural lipid, and 1-3 mol.% PEG-modified lipid (e.g., PEG-DMG or Compound P-I). For instance, in some embodiments, the lipid nanoparticle (“LNP-1”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-1 (ii) 35-45 mol.% sterol (e.g., cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). For instance, in some embodiments, the lipid nanoparticle (“LNP-1A”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-1 (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. For instance, in some embodiments, the lipid nanoparticle (“LNP-1B”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-1 (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the lipid nanoparticle (“LNP-2”) may comprise the following: (i) 45-50 mol.% Compound I-2; (ii) 35-45 mol.% sterol (e.g., Cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). In some embodiments, the lipid nanoparticle (“LNP-2A”) may comprise the following: (i) 45-50 mol.% Compound I-2; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. For instance, in some embodiments, the lipid nanoparticle (“LNP-2B”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-2; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the lipid nanoparticle (“LNP-3”) may comprise the following: (i) 45-50 mol.% Compound I-3; (ii) 35-45 mol.% sterol (e.g., Cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). In some embodiments, the lipid nanoparticle (“LNP-3A”) may comprise the following: (i) 45-50 mol.% Compound I-3; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. In some embodiments, the lipid nanoparticle (“LNP-3B”) may comprise the following: (i) 45-50 mol.% Compound I-3; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the LNP has a polydispersity value of less than 0.4. In some embodiments, the LNP has a net neutral charge at a neutral pH. In some embodiments, the LNP has a mean diameter of 50-150 nm. In some embodiments, the LNP has a mean diameter of 80-100 nm. As generally defined herein, the term “lipid” refers to a small molecule that has hydrophobic or amphiphilic properties. Lipids may be naturally occurring or synthetic. Examples of classes of lipids include, but are not limited to, fats, waxes, sterol- containing metabolites, vitamins, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides, and prenol lipids. In some instances, the amphiphilic properties of some lipids lead them to form liposomes, vesicles, or membranes in aqueous media. In some embodiments, a lipid nanoparticle (LNP) may comprise an ionizable amino lipid. As used herein, the term “ionizable amino lipid” has its ordinary meaning in the art and may refer to a lipid comprising one or more charged moieties. In some embodiments, an ionizable amino lipid may be positively charged or negatively charged. An ionizable amino lipid may be positively charged, in which case it can be referred to as “cationic lipid”. In certain embodiments, an ionizable amino lipid molecule may comprise an amine group, and can be referred to as an ionizable amino lipid. As used herein, a “charged moiety” is a chemical moiety that carries a formal electronic charge, e.g., monovalent (+1, or -1), divalent (+2, or -2), trivalent (+3, or -3), etc. The charged moiety may be anionic (i.e., negatively charged) or cationic (i.e., positively charged). Examples of positively-charged moieties include amine groups (e.g., primary, secondary, and/or tertiary amines), ammonium groups, pyridinium group, guanidine groups, and imidizolium groups. In a particular embodiment, the charged moieties comprise amine groups. Examples of negatively- charged groups or precursors thereof, include carboxylate groups, sulfonate groups, sulfate groups, phosphonate groups, phosphate groups, hydroxyl groups, and the like. The charge of the charged moiety may vary, in some cases, with the environmental conditions, for example, changes in pH may alter the charge of the moiety, and/or cause the moiety to become charged or uncharged. In general, the charge density of the molecule may be selected as desired. It should be understood that the terms “charged” or “charged moiety” does not refer to a “partial negative charge" or “partial positive charge" on a molecule. The terms “partial negative charge" and “partial positive charge" are given their ordinary meaning in the art. A “partial negative charge" may result when a functional group comprises a bond that becomes polarized such that electron density is pulled toward one atom of the bond, creating a partial negative charge on the atom. Those of ordinary skill in the art will, in general, recognize bonds that can become polarized in this way. The ionizable amino lipid is sometimes referred to in the art as an “ionizable cationic lipid”. In some embodiments, the ionizable amino lipid may have a positively charged hydrophilic head and a hydrophobic tail that are connected via a linker structure. In addition to these, an ionizable amino lipid may also be a lipid including a cyclic amine group. In some embodiments, the ionizable amino lipid may be selected from, but not limited to, an ionizable amino lipid described in International Publication Nos. WO2013086354 and WO2013116126; the contents of each of which are herein incorporated by reference in their entirety. In yet another embodiment, the ionizable amino lipid may be selected from, but not limited to, Formula CLI-CLXXXXII of US Patent No.7,404,969; each of which is herein incorporated by reference in their entirety. In some embodiments, the lipid may be a cleavable lipid such as those described in International Publication No. WO2012170889, herein incorporated by reference in its entirety. In some embodiments, the lipid may be synthesized by methods known in the art and/or as described in International Publication Nos. WO2013086354; the contents of each of which are herein incorporated by reference in their entirety. Nanoparticle compositions can be characterized by a variety of methods. For example, microscopy (e.g., transmission electron microscopy or scanning electron microscopy) can be used to examine the morphology and size distribution of a nanoparticle composition. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) can be used to measure zeta potentials. Dynamic light scattering can also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) can also be used to measure multiple characteristics of a nanoparticle composition, such as particle size, polydispersity index, and zeta potential. The size of the nanoparticles can help counter biological reactions such as, but not limited to, inflammation, or can increase the biological effect of the polynucleotide. As used herein, “size” or “mean size” in the context of nanoparticle compositions refers to the mean diameter of a nanoparticle composition. In some embodiments, the polynucleotide encoding a polypeptide are formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm, about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and/or about 90 to about 100 nm. In some embodiments, the nanoparticles have a diameter from about 10 to 500 nm. In some embodiments, the nanoparticle has a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. In some embodiments, the largest dimension of a nanoparticle composition is 1 µm or shorter (e.g., 1 µm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 175 nm, 150 nm, 125 nm, 100 nm, 75 nm, 50 nm, or shorter). A nanoparticle composition can be relatively homogenous. A polydispersity index can be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the nanoparticle composition. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A nanoparticle composition can have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the polydispersity index of a nanoparticle composition disclosed herein can be from about 0.10 to about 0.20. The zeta potential of a nanoparticle composition can be used to indicate the electrokinetic potential of the composition. For example, the zeta potential can describe the surface charge of a nanoparticle composition. Nanoparticle compositions with relatively low charges, positive or negative, are generally desirable, as more highly charged species can interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a nanoparticle composition disclosed herein can be from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about 10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about 0 mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 0 mV to about 100 mV, from about 0 mV to about 90 mV, from about 0 mV to about 80 mV, from about 0 mV to about 70 mV, from about 0 mV to about 60 mV, from about 0 mV to about 50 mV, from about 0 mV to about 40 mV, from about 0 mV to about 30 mV, from about 0 mV to about 20 mV, from about 0 mV to about 10 mV, from about 10 mV to about 100 mV, from about 10 mV to about 90 mV, from about 10 mV to about 80 mV, from about 10 mV to about 70 mV, from about 10 mV to about 60 mV, from about 10 mV to about 50 mV, from about 10 mV to about 40 mV, from about 10 mV to about 30 mV, from about 10 mV to about 20 mV, from about 20 mV to about 100 mV, from about 20 mV to about 90 mV, from about 20 mV to about 80 mV, from about 20 mV to about 70 mV, from about 20 mV to about 60 mV, from about 20 mV to about 50 mV, from about 20 mV to about 40 mV, from about 20 mV to about 30 mV, from about 30 mV to about 100 mV, from about 30 mV to about 90 mV, from about 30 mV to about 80 mV, from about 30 mV to about 70 mV, from about 30 mV to about 60 mV, from about 30 mV to about 50 mV, from about 30 mV to about 40 mV, from about 40 mV to about 100 mV, from about 40 mV to about 90 mV, from about 40 mV to about 80 mV, from about 40 mV to about 70 mV, from about 40 mV to about 60 mV, and from about 40 mV to about 50 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 10 mV to about 50 mV, from about 15 mV to about 45 mV, from about 20 mV to about 40 mV, and from about 25 mV to about 35 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be about 10 mV, about 20 mV, about 30 mV, about 40 mV, about 50 mV, about 60 mV, about 70 mV, about 80 mV, about 90 mV, and about 100 mV. The term “encapsulation efficiency” of a polynucleotide describes the amount of the polynucleotide that is encapsulated by or otherwise associated with a nanoparticle composition after preparation, relative to the initial amount provided. As used herein, “encapsulation” can refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement. Encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency can be measured, for example, by comparing the amount of the polynucleotide in a solution containing the nanoparticle composition before and after breaking up the nanoparticle composition with one or more organic solvents or detergents. Fluorescence can be used to measure the amount of free polynucleotide in a solution. For the nanoparticle compositions described herein, the encapsulation efficiency of a polynucleotide can be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency can be at least 80%. In certain embodiments, the encapsulation efficiency can be at least 90%. The amount of a polynucleotide present in a pharmaceutical composition disclosed herein can depend on multiple factors such as the size of the polynucleotide, desired target and/or application, or other properties of the nanoparticle composition as well as on the properties of the polynucleotide. For example, the amount of an mRNA useful in a nanoparticle composition can depend on the size (expressed as length, or molecular mass), sequence, and other characteristics of the mRNA. The relative amounts of a polynucleotide in a nanoparticle composition can also vary. The relative amounts of the lipid composition and the polynucleotide present in a lipid nanoparticle composition of the present disclosure can be optimized according to considerations of efficacy and tolerability. For compositions including an mRNA as a polynucleotide, the N:P ratio can serve as a useful metric. As the N:P ratio of a nanoparticle composition controls both expression and tolerability, nanoparticle compositions with low N:P ratios and strong expression are desirable. N:P ratios vary according to the ratio of lipids to RNA in a nanoparticle composition. In general, a lower N:P ratio is preferred. The one or more RNA, lipids, and amounts thereof can be selected to provide an N:P ratio from about 2:1 to about 30:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1. In certain embodiments, the N:P ratio can be from about 2:1 to about 8:1. In other embodiments, the N:P ratio is from about 5:1 to about 8:1. In certain embodiments, the N:P ratio is between 5:1 and 6:1. In one specific aspect, the N:P ratio is about is about 5.67:1. In addition to providing nanoparticle compositions, the present disclosure also provides methods of producing lipid nanoparticles comprising encapsulating a polynucleotide. Such method comprises using any of the pharmaceutical compositions disclosed herein and producing lipid nanoparticles in accordance with methods of production of lipid nanoparticles known in the art. See, e.g., Wang et al. (2015) “Delivery of oligonucleotides with lipid nanoparticles” Adv. Drug Deliv. Rev.87:68-80; Silva et al. (2015) “Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles” Curr. Pharm. Technol.16: 940-954; Naseri et al. (2015) “Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application” Adv. Pharm. Bull.5:305-13; Silva et al. (2015) “Lipid nanoparticles for the delivery of biopharmaceuticals” Curr. Pharm. Biotechnol.16:291-302, and references cited therein. In some embodiments, the LNP formulations described herein can additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in U.S. Pub. No. US20050222064, herein incorporated by reference in its entirety. The LNP formulations can further contain a phosphate conjugate. The phosphate conjugate can increase in vivo circulation times and/or increase the targeted delivery of the nanoparticle. Phosphate conjugates can be made by the methods described in, e.g., Intl. Pub. No. WO2013033438 or U.S. Pub. No. US20130196948. The LNP formulation can also contain a polymer conjugate (e.g., a water-soluble conjugate) as described in, e.g., U.S. Pub. Nos. US20130059360, US20130196948, and US20130072709. Each of the references is herein incorporated by reference in its entirety. The LNP formulations can comprise a conjugate to enhance the delivery of nanoparticles of the present disclosure in a subject. Further, the conjugate can inhibit phagocytic clearance of the nanoparticles in a subject. In some embodiments, the conjugate can be a "self" peptide designed from the human membrane protein CD47 (e.g., the "self" particles described by Rodriguez et al, Science 2013339, 971-975, herein incorporated by reference in its entirety). As shown by Rodriguez et al., the self peptides delayed macrophage-mediated clearance of nanoparticles which enhanced delivery of the nanoparticles. The LNP formulations can comprise a carbohydrate carrier. As a non-limiting example, the carbohydrate carrier can include, but is not limited to, an anhydride- modified phytoglycogen or glycogen-type material, phytoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin (e.g., Intl. Pub. No. WO2012109121, herein incorporated by reference in its entirety). The LNP formulations can be coated with a surfactant or polymer to improve the delivery of the particle. In some embodiments, the LNP can be coated with a hydrophilic coating such as, but not limited to, PEG coatings and/or coatings that have a neutral surface charge as described in U.S. Pub. No. US20130183244, herein incorporated by reference in its entirety. The LNP formulations can be engineered to alter the surface properties of particles so that the lipid nanoparticles can penetrate the mucosal barrier as described in U.S. Pat. No.8,241,670 or Intl. Pub. No. WO2013110028, each of which is herein incorporated by reference in its entirety. The LNP engineered to penetrate mucus can comprise a polymeric material (i.e., a polymeric core) and/or a polymer-vitamin conjugate and/or a tri-block co-polymer. The polymeric material can include, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, poly(styrenes), polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. LNP engineered to penetrate mucus can also include surface altering agents such as, but not limited to, polynucleotides, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as for example dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin, polyethylene glycol and poloxamer), mucolytic agents (e.g., N-acetylcysteine, mugwort, bromelain, papain, clerodendrum, acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin β4 dornase alfa, neltenexine, erdosteine) and various DNases including rhDNase. In some embodiments, the mucus penetrating LNP can be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation can be hypotonic for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations can be found in, e.g., Intl. Pub. No. WO2013110028, herein incorporated by reference in its entirety. In some embodiments, the polynucleotide described herein is Formulated as a lipoplex, such as, without limitation, the ATUPLEXTM system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECTTM from STEMGENT® (Cambridge, MA), and polyethylenimine (PEI) or protamine-based targeted and non-targeted delivery of nucleic acids (Aleku et al. Cancer Res.200868:9788-9798; Strumberg et al. Int J Clin Pharmacol Ther 201250:76-78; Santel et al., Gene Ther 200613:1222-1234; Santel et al., Gene Ther 200613:1360-1370; Gutbier et al., Pulm Pharmacol. Ther.201023:334- 344; Kaufmann et al. Microvasc Res 201080:286-293Weide et al. J Immunother.2009 32:498-507; Weide et al. J Immunother.200831:180-188; Pascolo Expert Opin. Biol. Ther.4:1285-1294; Fotin-Mleczek et al., 2011 J. Immunother.34:1-15; Song et al., Nature Biotechnol.2005, 23:709-717; Peer et al., Proc Natl Acad Sci U S A.2007 6;104:4095-4100; deFougerolles Hum Gene Ther.200819:125-132; all of which are incorporated herein by reference in its entirety). In some embodiments, the polynucleotides described herein are Formulated as a solid lipid nanoparticle (SLN), which can be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and can be stabilized with surfactants and/or emulsifiers. Exemplary SLN can be those as described in Intl. Pub. No. WO2013105101, herein incorporated by reference in its entirety. In some embodiments, the polynucleotides described herein can be Formulated for controlled release and/or targeted delivery. As used herein, "controlled release" refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome. In some embodiments, the polynucleotides can be encapsulated into a delivery agent described herein and/or known in the art for controlled release and/or targeted delivery. As used herein, the term "encapsulate" means to enclose, surround or encase. As it relates to the formulation of the compounds of the present disclosure, encapsulation can be substantial, complete or partial. The term "substantially encapsulated" means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or greater than 99% of the pharmaceutical composition or compound of the present disclosure can be enclosed, surrounded or encased within the delivery agent. "Partial encapsulation" or “partially encapsulate” means that less than 10, 10, 20, 30, 4050 or less of the pharmaceutical composition or compound of the present disclosure can be enclosed, surrounded or encased within the delivery agent. Advantageously, encapsulation can be determined by measuring the escape or the activity of the pharmaceutical composition or compound of the present disclosure using fluorescence and/or electron micrograph. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, or greater than 99% of the pharmaceutical composition or compound of the present disclosure are encapsulated in the delivery agent. In some embodiments, the polynucleotides described herein can be encapsulated in a therapeutic nanoparticle, referred to herein as "therapeutic nanoparticle polynucleotides." Therapeutic nanoparticles can be Formulated by methods described in, e.g., Intl. Pub. Nos. WO2010005740, WO2010030763, WO2010005721, WO2010005723, and WO2012054923; and U.S. Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286, US20120288541, US20120140790, US20130123351 and US20130230567; and U.S. Pat. Nos.8,206,747, 8,293,276, 8,318,208 and 8,318,211, each of which is herein incorporated by reference in its entirety. In some embodiments, the therapeutic nanoparticle polynucleotide can be Formulated for sustained release. As used herein, "sustained release" refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time can include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle of the polynucleotides described herein can be Formulated as disclosed in Intl. Pub. No. WO2010075072 and U.S. Pub. Nos. US20100216804, US20110217377, US20120201859 and US20130150295, each of which is herein incorporated by reference in their entirety. In some embodiments, the therapeutic nanoparticle polynucleotide can be Formulated to be target specific, such as those described in Intl. Pub. Nos. WO2008121949, WO2010005726, WO2010005725, WO2011084521 and WO2011084518; and U.S. Pub. Nos. US20100069426, US20120004293 and US20100104655, each of which is herein incorporated by reference in its entirety. The LNPs can be prepared using microfluidic mixers or micromixers. Exemplary microfluidic mixers can include, but are not limited to, a slit interdigital micromixer including, but not limited to those manufactured by Microinnova (Allerheiligen bei Wildon, Austria) and/or a staggered herringbone micromixer (SHM) (see Zhigaltsevet al., "Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing," Langmuir 28:3633-40 (2012); Belliveau et al., "Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA," Molecular Therapy-Nucleic Acids.1:e37 (2012); Chen et al., "Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation," J. Am. Chem. Soc.134(16):6948-51 (2012); each of which is herein incorporated by reference in its entirety). Exemplary micromixers include Slit Interdigital Microstructured Mixer (SIMM-V2) or a Standard Slit Interdigital Micro Mixer (SSIMM) or Caterpillar (CPMM) or Impinging-jet (IJMM,) from the Institut für Mikrotechnik Mainz GmbH, Mainz Germany. In some embodiments, methods of making LNP using SHM further comprise mixing at least two input streams wherein mixing occurs by microstructure-induced chaotic advection (MICA). According to this method, fluid streams flow through channels present in a herringbone pattern causing rotational flow and folding the fluids around each other. This method can also comprise a surface for fluid mixing wherein the surface changes orientations during fluid cycling. Methods of generating LNPs using SHM include those disclosed in U.S. Pub. Nos. US20040262223 and US20120276209, each of which is incorporated herein by reference in their entirety. In some embodiments, the polynucleotides described herein can be Formulated in lipid nanoparticles using microfluidic technology (see Whitesides, George M., "The Origins and the Future of Microfluidics," Nature 442: 368-373 (2006); and Abraham et al., "Chaotic Mixer for Microchannels," Science 295: 647-651 (2002); each of which is herein incorporated by reference in its entirety). In some embodiments, the polynucleotides can be Formulated in lipid nanoparticles using a micromixer chip such as, but not limited to, those from Harvard Apparatus (Holliston, MA) or Dolomite Microfluidics (Royston, UK). A micromixer chip can be used for rapid mixing of two or more fluid streams with a split and recombine mechanism. In some embodiments, the polynucleotides described herein can be Formulated in lipid nanoparticles having a diameter from about 1 nm to about 100 nm such as, but not limited to, about 1 nm to about 20 nm, from about 1 nm to about 30 nm, from about 1 nm to about 40 nm, from about 1 nm to about 50 nm, from about 1 nm to about 60 nm, from about 1 nm to about 70 nm, from about 1 nm to about 80 nm, from about 1 nm to about 90 nm, from about 5 nm to about from 100 nm, from about 5 nm to about 10 nm, about 5 nm to about 20 nm, from about 5 nm to about 30 nm, from about 5 nm to about 40 nm, from about 5 nm to about 50 nm, from about 5 nm to about 60 nm, from about 5 nm to about 70 nm, from about 5 nm to about 80 nm, from about 5 nm to about 90 nm, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and/or about 90 to about 100 nm. In some embodiments, the lipid nanoparticles can have a diameter from about 10 to 500 nm. In some embodiments, the lipid nanoparticle can have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. In some embodiments, the polynucleotides can be delivered using smaller LNPs. Such particles can comprise a diameter from below 0.1 µm up to 100 nm such as, but not limited to, less than 0.1 µm, less than 1.0 µm, less than 5µm, less than 10 µm, less than 15 um, less than 20 um, less than 25 um, less than 30 um, less than 35 um, less than 40 um, less than 50 um, less than 55 um, less than 60 um, less than 65 um, less than 70 um, less than 75 um, less than 80 um, less than 85 um, less than 90 um, less than 95 um, less than 100 um, less than 125 um, less than 150 um, less than 175 um, less than 200 um, less than 225 um, less than 250 um, less than 275 um, less than 300 um, less than 325 um, less than 350 um, less than 375 um, less than 400 um, less than 425 um, less than 450 um, less than 475 um, less than 500 um, less than 525 um, less than 550 um, less than 575 um, less than 600 um, less than 625 um, less than 650 um, less than 675 um, less than 700 um, less than 725 um, less than 750 um, less than 775 um, less than 800 um, less than 825 um, less than 850 um, less than 875 um, less than 900 um, less than 925 um, less than 950 um, or less than 975 um. The nanoparticles and microparticles described herein can be geometrically engineered to modulate macrophage and/or the immune response. The geometrically engineered particles can have varied shapes, sizes and/or surface charges to incorporate the polynucleotides described herein for targeted delivery such as, but not limited to, pulmonary delivery (see, e.g., Intl. Pub. No. WO2013082111, herein incorporated by reference in its entirety). Other physical features the geometrically engineering particles can include, but are not limited to, fenestrations, angled arms, asymmetry and surface roughness, charge that can alter the interactions with cells and tissues. In some embodiment, the nanoparticles described herein are stealth nanoparticles or target-specific stealth nanoparticles such as, but not limited to, those described in U.S. Pub. No. US20130172406, herein incorporated by reference in its entirety. The stealth or target-specific stealth nanoparticles can comprise a polymeric matrix, which can comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates, polycyanoacrylates, or combinations thereof. Methods of Using Antagonistic CD28 Antibodies to Treat Autoimmunity Antagonistic CD28 antibodies of the disclosure, and nucleic acids encoding the same, can be used for the treatment of a wide array of immunological disorders. Antagonistic CD28 antibodies described herein, and nucleic acids encoding the same, can be administered to a subject, e.g., a mammalian subject, such as a human, in order to treat such conditions as autoimmune diseases. Without being limited by mechanism, antagonistic CD28 antibodies described herein, and nucleic acids encoding the same, can be administered to a mammalian subject, such as a human, to inhibit the proliferation of autoreactive T cells (e.g., T cells which respond to self-antigens (e.g., CD4+ and CD8+ T cells)). This response can have the effect of reducing populations of cytotoxic autoreactive T-lymphocytes (e.g., CD8+ T-cells) that are often associated with mounting an inappropriate immune response that can cause an immunological disorder. Antagonistic CD28 antibodies may, additionally or alternatively, directly kill autoreactive T cells, such as autoreactive CD8+ T cells, and may inhibit the activation and expansion of naive CD4+ and/or CD8+ T cells into autoreactive CD4+ and/or CD8+ T cells, as described above. In specific examples, antagonistic CD28 antibodies described herein, and nucleic acids encoding the same, may be administered to a subject, e.g., a mammalian subject, such as a human) suffering from allograft rejection or a graft-versus-host disease (GVHD). Exemplary graft-versus-host diseases that can be treated using the compositions and methods of the disclosure include those that arise from a bone marrow transplant, as well as from the transplantation of blood cells, such as hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T-cells, B-cells, natural killer cells, and/or dendritic cells. Antagonistic CD28 antibodies described, and nucleic acids encoding the same, can also be administered to a subject, e.g., a mammalian subject, such as a human, suffering from an immunological disease, e.g., in order to bind a CD28 receptor on the surface of an autoreactive T-cell and induce apoptosis, and/or to inhibit T cell expansion and thus suppress the activity of inappropriately reactive cytotoxic T-lymphocytes in the patient. Antibodies of the disclosure, and nucleic acids encoding the same, can be administered to a subject, e.g., via any of the routes of administration described herein. Routes of Administration and Dosing Antagonistic CD28 antibodies of the disclosure, and nucleic acids encoding the same, can be administered to a subject (e.g., a mammalian subject, such as a human) by a variety of routes. In some embodiments, the antibody or nucleic acid is administered to the subject intravenously, subcutaneously, intramuscularly, parenterally, intrathecally, intracerebroventricularly, transdermally, or orally. The most suitable route for administration in any given case will depend on the particular therapeutic agent administered, the patient, pharmaceutical formulation methods, and various patient-specific parameters, such as the patient's age, body weight, sex, severity of the diseases being treated, the patient’s diet, and the patient’s excretion rate. Kits Containing Antagonistic CD28 Antibodies Also included herein are kits that contain antagonistic CD28 antibodies and/or nucleic acids encoding the same. In some embodiments, the kits provided herein contain one or more cells engineered to express and secrete an antagonistic CD28 antibody of the disclosure, such as a cell containing a nucleic acid molecule of the disclosure. A kit described herein may include reagents that can be used to produce a pharmaceutical composition of the disclosure. Optionally, kits described herein may include reagents that can induce the expression of antagonistic CD28 antibodies within cells (e.g., mammalian cells). Other kits described herein may include tools for engineering a prokaryotic or eukaryotic cell (e.g., a CHO cell or a BL21(DE3) E. Coli cell) so as to express and secrete an antagonistic CD28 antibody described herein. For example, a kit may contain CHO cells stored in an appropriate media and optionally frozen according to methods known in the art. The kit may also contain a nucleic acid encoding the desired antibody, as well as reagents for expressing the antibody in the cell. A kit described herein may also provide an antagonistic CD28 antibody of the disclosure, or a nucleic acid encoding the same, in combination with a package insert describing how the antibody or nucleic acid may be administered to a subject, for example, for the treatment of a disease or condition described herein. Definitions As used herein, the term “about” refers to a value that is no more than 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 nM to 5.5 nM. As used herein, the term “antagonistic CD28 antibody” refers to CD28 antibodies that are capable of suppressing or reducing activation of CD28 and/or one or more signal transduction pathways mediated by CD28. For example, antagonistic CD28 antibodies of the disclosure include antibodies that can reduce or inhibit the proliferation of a population of autoreactive T cells (e.g., autoreactive CD4+ and/or CD8+ T cells). Antagonistic CD28 antibodies of the disclosure may reduce or inhibit CD28 activation by binding CD28, e.g., so as to induce a conformational change that renders the protein biologically inactive. For instance, antagonistic CD28 antibodies of the disclosure may bind CD28 in a manner that prevents or reduces the interaction between CD28 and its cognate ligands, CD80 and CD86, thus preventing the induction CD28-mediated signaling. Antagonistic CD28 antibodies of the disclosure may be capable of reducing or inhibiting the proliferation of autoreactive CD4+ and/or CD8+ T cells. For example, in some embodiments, antagonistic CD28 antibodies of the disclosure are capable of suppressing the proliferation of autoreactive cytotoxic T lymphocytes (e.g., CD8+ T cells), such as by directly binding CD28 on the surface of an autoreactive cytotoxic T cell and inducing cell death. Unless otherwise noted, the term “antagonistic CD28 antibody” also includes antibody fragments, e.g., those described below, that retain the ability to bind CD28 and inhibit CD28 signal transduction. The term “antagonistic CD28 antibody” also refers to any protein or peptide-containing molecule that includes at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one CDR of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that is capable of specifically binding to CD28 and inhibiting CD28 function. Antagonistic CD28 antibodies of the disclosure also include antibody-like protein scaffolds, such as the tenth fibronectin type III domain (¹⁰Fn3), which contains BC, DE, and FG structural loops similar in structure and solvent accessibility to antibody CDRs. The tertiary structure of the ¹⁰Fn3 domain resembles that of the variable region of the IgG heavy chain, and one of skill in the art can graft, e.g., the CDRs of a CD28 monoclonal antibody onto the fibronectin scaffold by replacing residues of the BC, DE, and FG loops of ¹⁰Fn3 with residues from the CDRH-1, CDRH-2, or CDRH-3 regions of a CD28 monoclonal antibody. The use of ¹⁰Fn3 domains as scaffolds for epitope grafting is described, e.g., in WO 2000/034784, the disclosure of which is incorporated herein by reference. Additional scaffold proteins that may be used in conjunction with the compositions and methods of the disclosure include peptide-Fc fusion proteins (described, e.g., in WO 2012/122378; as well as in US 8,633,297; the disclosures of each of which are incorporated herein by reference). As used herein, the term “antibody” (Ab) refers to an immunoglobulin molecule, or a molecule having an immunoglobulin-like scaffold, that specifically binds to, or is immunologically reactive with, a particular antigen. The term “antibody” includes polyclonal, monoclonal, genetically engineered, and otherwise modified forms of antibodies, including, but not limited to, chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including e.g., Fab', F(ab')₂, Fab, Fv, recombinant IgG (rlgG) fragments, and scFv fragments. Moreover, unless otherwise indicated, the term “monoclonal antibody” (mAb) is meant to include both intact molecules, as well as antibody fragments (such as, for example, Fab and F(ab')₂ fragments) that are capable of specifically binding to a target protein. Fab and F(ab')₂ fragments lack the Fc fragment of an intact antibody, clear more rapidly from the circulation of the animal, and may have less non-specific tissue binding than an intact antibody (see Wahl et al., J. Nucl. Med.24:316, 1983; incorporated herein by reference). The term “antigen-binding fragment,” as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to a target antigen. The antigen-binding function of an antibody can be performed by fragments of a full- length antibody. The antibody fragments can be, e.g., a single-domain antibody (sdAb), Fab, F(ab’)₂, scFv, SMIP, diabody, a triabody, an affibody, an aptamer, or a domain antibody. Examples of binding fragments encompassed by the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the V_L, V_H, C_L, and C_H1 domains; (ii) a F(ab')₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V_H and C_H1 domains; (iv) a Fv fragment consisting of the V_L and V_H domains of a single arm of an antibody, (v) a dAb including V_H and V_L domains; (vi) a dAb fragment (Ward et al., Nature 341:544-546, 1989), which consists of a V_H domain; (vii) a dAb which consists of a V_H or a V_L domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, V_L and V_H, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the V_L and V_H regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426, 1988, and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in some embodiments, by chemical peptide synthesis procedures known in the art. As used herein, the term “bispecific antibodies” refers to monoclonal, often human or humanized antibodies that have binding specificities for at least two different antigens. Bispecific CD28 antibodies of the disclosure may have binding specificities that are directed towards CD28 and any other antigen, e.g., for a cell-surface protein, receptor, receptor subunit, or tissue-specific antigen. A bispecific antibody may also be an antibody or antigen-binding fragment thereof that includes two separate antigen- binding domains (e.g., two scFvs joined by a linker). The scFvs may bind the same antigen or different antigens. As used herein, the term “chimeric” antibody refers to an antibody having variable domain sequences (e.g., CDR sequences) derived from an immunoglobulin of one source organism, such as rat or mouse, and constant regions derived from an immunoglobulin of a different organism (e.g., a human, another primate, pig, goat, rabbit, hamster, cat, dog, guinea pig, member of the bovidae family (such as cattle, bison, buffalo, elk, and yaks, among others), cow, sheep, horse, or bison, among others). Methods for producing chimeric antibodies are known in the art. See, e.g., Morrison, 1985, Science 229(4719): 1202-7; Oi et al., 1986, BioTechniques 4:214-221; Gillies et al., 1985, J. Immunol. Methods 125:191-202; U.S. Pat. Nos.5,807,715; 4,816,567; and 4,816,397; incorporated herein by reference. As used herein, the term “complementarity determining region” or “CDR” refers to a hypervariable region found in the light chain and/or the heavy chain variable domains of an antibody. The more highly conserved portions of variable domains are called the framework regions (FRs). As is appreciated in the art, the amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. The disclosure includes antibodies comprising modifications in these hybrid hypervariable positions. The variable domains of native heavy and light chains each comprise four framework regions that primarily adopt a β-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the β-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md.1987; incorporated herein by reference). As used herein, numbering of immunoglobulin amino acid residues is performed according to the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise indicated. As used herein, the terms “conservative mutation,” “conservative substitution,” “conservative amino acid substitution,” and the like refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and/or steric volume. These properties are summarized for each of the twenty naturally-occurring amino acids in Table 8 below. Table 8. Representative physicochemical properties of naturally-occurring amino acids

From this table it is appreciated that the conservative amino acid families include, e.g., (i) G, A, V, L, I, P, and M; (ii) D and E; (iii) C, S and T; (iv) H, K and R; (v) N and Q; and (vi) F, Y and W. A conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg). As used herein, the term “conjugate” refers to a compound formed by the chemical bonding of a reactive functional group of one molecule with an appropriately reactive functional group of another molecule. Conjugates may additionally be produced, e.g., as two polypeptide domains covalently bound to one another as part of a single polypeptide chain that is synthesized by the translation of a single RNA transcript encoding both polypeptides in frame with one another. As used herein in the context of a CD28 antagonist, the term “construct” refers to a fusion protein containing a first polypeptide domain bound to a second polypeptide domain. The polypeptide domains may each independently be antagonist CD28 single chain polypeptides, for instance, as described herein. The first polypeptide domain may be covalently bound to the second polypeptide domain, for instance, by way of a linker, such as a peptide linker or a disulfide bridge, among others. Exemplary linkers that may be used to join the polypeptide domains of an antagonistic CD28 construct include, without limitation, those that are described in Leriche et al., Bioorg. Med. Chem., 20:571-582 (2012), the disclosure of which is incorporated herein by reference in its entirety. As used herein, the term “derivatized antibodies” refers to antibodies that are modified by a chemical reaction so as to cleave residues or add chemical moieties not native to an isolated antibody. Derivatized antibodies can be obtained by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by addition of known chemical protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of a variety of chemical modifications can be carried out by known techniques, including, without limitation, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. using established procedures. Additionally, the derivative can contain one or more non-natural amino acids, e.g., using amber suppression technology (see, e.g., US Patent No.6,964,859; incorporated herein by reference). As used herein, the term “diabodies” refers to bivalent antibodies comprising two polypeptide chains, in which each polypeptide chain includes V_H and V_L domains joined by a linker that is too short (e.g., a linker composed of five amino acids) to allow for intramolecular association of V_H and V_L domains on the same peptide chain. This configuration forces each domain to pair with a complementary domain on another polypeptide chain so as to form a homodimeric structure. Accordingly, the term “triabodies” refers to trivalent antibodies comprising three peptide chains, each of which contains one V_H domain and one V_L domain joined by a linker that is exceedingly short (e.g., a linker composed of 1-2 amino acids) to permit intramolecular association of V_H and V_L domains within the same peptide chain. In order to fold into their native structure, peptides configured in this way typically trimerize so as to position the V_H and V_L domains of neighboring peptide chains spatially proximal to one another to permit proper folding (see Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-48, 1993; incorporated herein by reference). As used herein, the term “endogenous” describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell). As used herein, the term “exogenous” describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is not found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell). Exogenous materials include those that are provided from an external source to an organism or to cultured matter extracted there from. As used herein, the term “framework region” or “FW region” includes amino acid residues that are adjacent to the CDRs. FW region residues may be present in, for example, human antibodies, rodent-derived antibodies (e.g., murine antibodies), humanized antibodies, primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), single-chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others. As used herein, the term “fusion protein” refers to a protein that is joined via a covalent bond to another molecule. A fusion protein can be chemically synthesized by, e.g., an amide-bond forming reaction between the N-terminus of one protein to the C- terminus of another protein. Alternatively, a fusion protein containing one protein covalently bound to another protein can be expressed recombinantly in a cell (e.g., a eukaryotic cell or prokaryotic cell) by expression of a polynucleotide encoding the fusion protein, for example, from a vector or the genome of the cell. A fusion protein may contain one protein that is covalently bound to a linker, which in turn is covalently bound to another molecule. Examples of linkers that can be used for the formation of a fusion protein include peptide- containing linkers, such as those that contain naturally occurring or non-naturally occurring amino acids. In some embodiments, it may be desirable to include D-amino acids in the linker, as these residues are not present in naturally-occurring proteins and are thus more resistant to degradation by endogenous proteases. Linkers can be prepared using a variety of strategies that are well known in the art, and depending on the reactive components of the linker, can be cleaved by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012). As used herein, the term “heterospecific antibodies” refers to monoclonal (e.g., human or humanized) antibodies that have binding specificities for at least two different antigens. Traditionally, the recombinant production of heterospecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein et al., Nature 305:537, 1983). Similar procedures are disclosed, e.g., in WO 93/08829, U.S. Pat. Nos.6,210,668; 6,193,967; 6,132,992; 6,106,833; 6,060,285; 6,037,453; 6,010,902; 5,989,530; 5,959,084; 5,959,083; 5,932,448; 5,833,985; 5,821,333; 5,807,706; 5,643,759, 5,601,819; 5,582,996, 5,496,549, 4,676,980, WO 91/00360, WO 92/00373, EP 03089, Traunecker et al., EMBO J.10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986); incorporated herein by reference. Heterospecific antibodies can include Fc mutations that enforce correct chain association in multi-specific antibodies, as described by Klein et al., mAbs 4(6):653-663, 2012; incorporated herein by reference. As used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, C_L, C_H domains (e.g., C_H1, C_H2, C_H3), hinge, (V_L, V_H)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. A human antibody can be produced in a human cell (e.g., by recombinant expression), or by a non-human animal or a prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes. Further, when a human antibody is a single-chain antibody, it can include a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. See U.S. Patent Nos.4,444,887 and 4,716,111; and PCT publications WO 1998/46645; WO 1998/50433; WO 1998/24893; WO 1998/16654; WO 1996/34096; WO 1996/33735; and WO 1991/10741; incorporated herein by reference. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. See, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; U.S. Patent Nos.5,413,923; 5,625, 126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598; incorporated by reference herein. As used herein, the term “humanized” antibodies refers to forms of non-human (e.g., murine) antibodies that are chimeric immunoglobulins, or immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')₂ or other target-binding subdomains of antibodies), which contain minimal sequences derived from non-human immunoglobulin. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin. All or substantially all of the FRs may also be those of a human immunoglobulin sequence. The humanized antibody may also contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art. See, e.g., Riechmann et al., Nature 332:323-7, 1988; U.S. Patent Nos: 5,530,101; 5,585,089; 5,693,761; 5,693,762; and 6,180,370 to Queen et al; EP239400; PCT publication WO 91/09967; U.S. Patent No.5,225,539; EP592106; and EP519596; the disclosure of each of which is incorporated herein by reference. As used herein, the term “lipid nanoparticle” refers to a transfer vehicle including one or more lipids (e.g., ionizable cationic lipids, non-cationic lipids, and PEG-modified lipids). Exemplary lipid nanoparticles are formulated to deliver one or more mRNA to one or more target cells. Examples of suitable lipids include, for example, the phosphatidyl compounds (e.g., phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides). Lipid nanoparticles may contain a ionizable cationic lipid, or a lipid species with a net positive charge at a selected pH (e.g., physiological pH), to encapsulate and/or enhance the delivery of mRNA into the target cells. As used herein, the terms “messenger RNA” or “mRNA” refer to any polynucleotide which encodes a polypeptide of interest and which is capable of being translated to produce the encoded polypeptide of interest in vitro, in vivo, in situ, or ex vivo. Traditionally, the basic components of an mRNA molecule include a coding region, a 5’UTR, a 3’UTR, a 5’ cap, and a poly-A tail. As used herein, the terms “modified messenger RNA” or “modified mRNA” refer to mRNA polynucleotides that include naturally occurring and/or non-naturally occurring modifications, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage, or to the phosphodiester backbone). Non-natural modified nucleotides may be introduced during synthesis of post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleoside linkage, purine or pyrimidine base, or sugar. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a polynucleotide may be chemically modified. As used herein, the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced. As used herein, the term “multi-specific antibodies” refers to antibodies that exhibit affinity for more than one target antigen. Multi-specific antibodies can have structures similar to full immunoglobulin molecules and include Fc regions, for example IgG Fc regions. Such structures can include, but not limited to, IgG-Fv, IgG-(scFv)₂, DVD-Ig, (scFv)₂-(scFv)₂-Fc and (scFv)₂-Fc-(scFv)₂. In case of IgG-(scFv)₂, the scFv can be attached to either the N-terminal or the C- terminal end of either the heavy chain or the light chain. Exemplary multi-specific molecules that include Fc regions and into which CD28 antibodies or antigen-binding fragments thereof can be incorporated have been reviewed by Kontermann, 2012, mAbs 4(2):182-197, Yazaki et al., 2013, Protein Engineering, Design & Selection 26(3):187- 193, and Grote et al., 2012, in Proetzel & Ebersbach (eds.), Antibody Methods and Protocols, Methods in Molecular Biology vol. 901, chapter 16:247-263; incorporated herein by reference. In some embodiments, antibody fragments can be components of multi-specific molecules without Fc regions, based on fragments of IgG or DVD or scFv. Exemplary multi-specific molecules that lack Fc regions and into which antibodies or antibody fragments can be incorporated include scFv dimers (diabodies), trimers (triabodies) and tetramers (tetrabodies), Fab dimers (conjugates by adhesive polypeptide or protein domains) and Fab trimers (chemically conjugated), are described by Hudson and Souriau, 2003, Nature Medicine 9:129-134; incorporated herein by reference. As used herein, the term “nucleic acid” includes any compound containing a continuous segment of nucleosides joined by way of one or more internucleoside linkages (e.g., polymers of nucleosides linked by way of phosphodiester bonds). Exemplary nucleic acids include ribonucleic acids (RNA), deoxyribonucleic acids (DNA), threose nucleic acids (TNA), glycol nucleic acids (GNA), peptide nucleic acids (PNA), locked nucleic acids (LNA), or hybrids thereof. Nucleic acids also include RNAi inducers, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNAs, tRNAs, RNAs that induce triple spiral formation, aptamers, vectors, and the like. In a preferred embodiment, the nucleic acid is one or more modified messenger RNAs (modified mRNAs). As used herein, the terms “percent (%) sequence identity,” “percent (%) identity,” and the like, with respect to a reference polynucleotide or polypeptide sequence, is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows: 100 multiplied by (the fraction X/Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A. As used herein, the term “primatized antibody” refers to an antibody comprising framework regions from primate-derived antibodies and other regions, such as CDRs and/or constant regions, from antibodies of a non-primate source. Methods for producing primatized antibodies are known in the art. See e.g., U.S. Patent Nos. 5,658,570; 5,681,722; and 5,693,780; incorporated herein by reference. For instance, a primatized antibody or antigen-binding fragment thereof described herein can be produced by inserting the CDRs of a non-primate antibody or antigen-binding fragment thereof into an antibody or antigen-binding fragment thereof that contains one or more framework regions of a primate. As used herein, the term “operatively linked” in the context of a polynucleotide fragment is intended to mean that the two polynucleotide fragments are joined such that the amino acid sequences encoded by the two polynucleotide fragments remain in- frame. As used herein, the term “pharmacokinetic profile” refers to the absorption, distribution, metabolism, and clearance of a therapeutic agent (e.g., a polypeptide, such as an antagonistic CD28 antibody, antigen-binding fragment thereof, single-chain polypeptide, or construct of the disclosure) over time following administration of the drug to a patient. As used herein, the term “regulatory sequence” includes promoters, enhancers, and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation, e.g., of antibody chain genes. Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185 (Academic Press, San Diego, CA, 1990); incorporated herein by reference. As used herein, the term “scFv” refers to a single-chain Fv antibody in which the variable domains of the heavy chain and the light chain from an antibody have been joined to form one chain. ScFv fragments contain a single polypeptide chain that includes the variable region of an antibody light chain (V_L) (e.g., CDR-L1, CDR-L2, and/or CDR-L3) and the variable region of an antibody heavy chain (V_H) (e.g., CDR-H1, CDR-H2, and/or CDR-H3) separated by a linker. The linker that joins the V_L and V_H regions of a scFv fragment can be a peptide linker composed of proteinogenic amino acids. Alternative linkers can be used to so as to increase the resistance of the scFv fragment to proteolytic degradation (e.g., linkers containing D-amino acids), in order to enhance the solubility of the scFv fragment (e.g., hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (e.g., a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to attenuate the immunogenicity of the scFv fragment (e.g., linkers containing glycosylation sites). ScFv molecules are known in the art and are described, e.g., in US patent 5,892,019, Flo et al., (Gene 77:51, 1989); Bird et al., (Science 242:423, 1988); Pantoliano et al., (Biochemistry 30:10117, 1991); Milenic et al., (Cancer Research 51:6363, 1991); and Takkinen et al., (Protein Engineering 4:837, 1991). The V_L and V_H domains of a scFv molecule can be derived from one or more antibody molecules. It will also be understood by one of ordinary skill in the art that the variable regions of the scFv molecules described herein can be modified such that they vary in amino acid sequence from the antibody molecule from which they were derived. For example, in one embodiment, nucleotide or amino acid substitutions leading to conservative substitutions or changes at amino acid residues can be made (e.g., in CDR and/or framework residues). Alternatively or in addition, mutations are made to CDR amino acid residues to optimize antigen binding using art recognized techniques. ScFv fragments are described, for example, in WO 2011/084714; incorporated herein by reference. As used herein, the terms "single-domain antibody," "sdAb," “nanobody,” and “VHH antibody” are used interchangeably to refer to a single-chain antibody fragment that contains only a single heavy-chain variable domain. Unlike a traditional, full-length antibody, which includes heavy chains and light chains, each containing a corresponding variable domain (i.e., a heavy chain variable domain, V_H, and a light chain variable domain, V_L) having three CDRs, a single-domain antibody only includes one heavy-chain variable domain having a total of three CDRs (referred to herein as CDR-H1, CDR-H2, and CDR-H3). As used herein, the phrase “specifically binds” refers to a binding reaction which is determinative of the presence of an antigen in a heterogeneous population of proteins and other biological molecules that is recognized, e.g., by an antibody or antigen- binding fragment thereof, with particularity. An antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a K_D of less than 100 nM. For example, an antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a K_D of up to 100 nM (e.g., between 1 pM and 100 nM). An antibody or antigen-binding fragment thereof that does not exhibit specific binding to a particular antigen or epitope thereof will exhibit a K_D of greater than 100 nM (e.g., greater than 500 nm, 1 µM, 100 µM, 500 µM, or 1 mM) for that particular antigen or epitope thereof. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein or carbohydrate. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein or carbohydrate. See, Harlow & Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1988) and Harlow & Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1999), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity. As used herein, the terms “subject” and “patient” refer to an organism that receives treatment (e.g., by administration of an antagonistic CD28 polypeptide, such as an antibody, antigen-binding fragment thereof, single-chain polypeptide, or construct described herein) for a particular disease or condition, such as an immunological disorder (e.g., an autoimmune disease). Examples of subjects and patients include mammals, such as humans, primates, pigs, goats, rabbits, hamsters, cats, dogs, guinea pigs, members of the bovidae family (such as cattle, bison, buffalo, and yaks, among others), sheep, and horses, among others, receiving treatment for immunological diseases or conditions, for example, autoimmune disorders (e.g., allograft rejection) and graft-versus-host disease, among others. A patient that may be treated using the compositions and methods described herein may have an established disease (e.g., an established immunological disorder, such as an autoimmune disease), in which case the patient has been diagnosed as having the disease and has shown symptoms of the disease for a prolonged period of time (e.g., over the course of days, weeks, months, or years). Alternatively, a patient may be symptomatic for a particular disease, such as an immunological disorder described herein, but has yet to be diagnosed with the disease by a physician. Other patients that may be treated using the compositions and methods described herein include those that have been diagnosed as having an immunological disorder, and may or may not be showing symptoms of the disease as of yet. For example, a patient eligible for treatment with the compositions and methods described herein may be described as diagnosed but asymptomatic if the patient has received a diagnosis of an immunological disorder, such as multiple sclerosis, e.g., by detection of depleted myelin sheath around one or more neurons of the patient due to the activity of autoreactive T cells, even though the patient may not yet be showing symptoms of multiple sclerosis (e.g., lack of balance, reduced cognitive performance, blurred vision, or attenuated coordination, among others). Another example of a patient that has been diagnosed with an immunological condition but is asymptomatic includes a patient that has been diagnosed with rheumatoid arthritis, e.g., by the detection of autoreactive T cells in a lymph sample isolated from the patient, even though the patient has not yet presented with the symptoms associated with this disease, such as joint pain, joint stiffness, and a decrease in the muscle range or movement, among others. As used herein, the term “transfection” refers to any of a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, lipofection, calcium- phosphate precipitation, DEAE- dextran transfection and the like. As used herein, the terms “treat” or “treatment” refer to therapeutic treatment, in which the object is to inhibit or slow down (lessen) an undesired physiological change or disorder, such as an immunological disorder (e.g., autoimmune disorders (e.g., allograft rejection) and graft-versus-host disease, among others). Beneficial or desired clinical results of treatment include, without limitation, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Those in need of treatment include those already having the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be inhibited. As used herein, the terms “cluster of differentiation 28” or “CD28” or “CD28S” refer to a type I transmembrane protein expressed on the surface of the majority of naïve autoreactive CD4+ and/or CD8+ T cells. As used herein the term “variable region CDR” includes amino acids in a CDR or complementarity determining region as identified using sequence or structure-based methods. As used herein, the term “CDR” or “complementarity determining region” refers to the noncontiguous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem.252:6609-6616, 1977 and Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91 -3242, 1991; by Chothia et al., (J. Mol. Biol.196:901- 917, 1987), and by MacCallum et al., (J. Mol. Biol.262:732-745, 1996) where the definitions include overlapping or subsets of amino acid residues when compared against each other. In certain embodiments, the term “CDR” is a CDR as defined by Kabat based on sequence comparisons. As used herein, the term “vector” includes a nucleic acid vector, e.g., a DNA vector, such as a plasmid, an RNA vector, virus or other suitable replicon (e.g., viral vector). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Examples of such expression vectors are disclosed in, e.g., WO 1994/11026; incorporated herein by reference. Expression vectors described herein contain a polynucleotide sequence as well as, e.g., additional sequence elements used for the expression of proteins and/or the integration of these polynucleotide sequences into the genome of a mammalian cell. Certain vectors that can be used for the expression of antibodies and antibody fragments described herein include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of antibodies and antibody fragments contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements include, e.g., 5’ and 3’ untranslated regions, an internal ribosomal entry site (IRES), and polyadenylation signal site in order to direct efficient transcription of the gene carried on the expression vector. The expression vectors described herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker include genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, or nourseothricin. As used herein, the term “V_H” refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, or Fab. References to “V_L” refer to the variable region of an immunoglobulin light chain, including the light chain of an Fv, scFv, dsFv or Fab. Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific target, immunoglobulins include both antibodies and other antibody-like molecules which lack target specificity. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain of a native antibody has at the amino terminus a variable domain (V_H) followed by a number of constant domains. Each light chain of a native antibody has a variable domain at the amino terminus (V_L) and a constant domain at the carboxy terminus. As used herein, the term "alkyl", "alkyl group", or "alkylene" means a linear or branched, saturated hydrocarbon including one or more carbon atoms (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms), which is optionally substituted. The notation "C_1-14 alkyl" means an optionally substituted linear or branched, saturated hydrocarbon including 1-14 carbon atoms. Unless otherwise specified, an alkyl group described herein refers to both unsubstituted and substituted alkyl groups. As used herein, the term "alkenyl", "alkenyl group", or "alkenylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one double bond, which is optionally substituted. The notation "C₂-₁₄ alkenyl" means an optionally substituted linear or branched hydrocarbon including 2-14 carbon atoms and at least one carbon-carbon double bond. An alkenyl group may include one, two, three, four, or more carbon-carbon double bonds. For example, C₁₈ alkenyl may include one or more double bonds. A C₁₈ alkenyl group including two double bonds may be a linoleyl group. Unless otherwise specified, an alkenyl group described herein refers to both unsubstituted and substituted alkenyl groups. As used herein, the term "alkynyl", "alkynyl group", or "alkynylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one carbon- carbon triple bond, which is optionally substituted. The notation "C_2-14 alkynyl" means an optionally substituted linear or branched hydrocarbon including 2-14 carbon atoms and at least one carbon-carbon triple bond. An alkynyl group may include one, two, three, four, or more carbon-carbon triple bonds. For example, C₁₈ alkynyl may include one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group described herein refers to both unsubstituted and substituted alkynyl groups. As used herein, the term "carbocycle" or "carbocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings of carbon atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty membered rings. The notation "C_3-6 carbocycle" means a carbocycle including a single ring having 3-6 carbon atoms. Carbocycles may include one or more carbon-carbon double or triple bonds and may be non-aromatic or aromatic (e.g., cycloalkyl or aryl groups). Examples of carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and 1,2 dihydronaphthyl groups. The term "cycloalkyl" as used herein means a non-aromatic carbocycle and may or may not include any double or triple bond. Unless otherwise specified, carbocycles described herein refers to both unsubstituted and substituted carbocycle groups, i.e., optionally substituted carbocycles. As used herein, the term "heterocycle" or "heterocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings, where at least one ring includes at least one heteroatom. Heteroatoms may be, for example, nitrogen, oxygen, or sulfur atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen membered rings. Heterocycles may include one or more double or triple bonds and may be non-aromatic or aromatic (e.g., heterocycloalkyl or heteroaryl groups). Examples of heterocycles include imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, thiazolidinyl, pyrazolidinyl, pyrazolyl, isoxazolidinyl, isoxazolyl, isothiazolidinyl, isothiazolyl, morpholinyl, pyrrolyl, pyrrolidinyl, furyl, tetrahydrofuryl, thiophenyl, pyridinyl, piperidinyl, quinolyl, and isoquinolyl groups. The term "heterocycloalkyl" as used herein means a non-aromatic heterocycle and may or may not include any double or triple bond. Unless otherwise specified, heterocycles described herein refers to both unsubstituted and substituted heterocycle groups, i.e., optionally substituted heterocycles. As used herein, the term "heteroalkyl", "heteroalkenyl", or "heteroalkynyl", refers respectively to an alkyl, alkenyl, alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. Unless otherwise specified, heteroalkyls, heteroalkenyls, or heteroalkynyls described herein refers to both unsubstituted and substituted heteroalkyls, heteroalkenyls, or heteroalkynyls, i.e., optionally substituted heteroalkyls, heteroalkenyls, or heteroalkynyls. As used herein, a "biodegradable group" is a group that may facilitate faster metabolism of a lipid in a mammalian entity. A biodegradable group may be selected from the group consisting of, but is not limited to, -C(O)O-, -OC(O)-, -C(O)N(R')-, - N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, an aryl group, and a heteroaryl group. As used herein, an "aryl group" is an optionally substituted carbocyclic group including one or more aromatic rings. Examples of aryl groups include phenyl and naphthyl groups. As used herein, a "heteroaryl group" is an optionally substituted heterocyclic group including one or more aromatic rings. Examples of heteroaryl groups include pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, and thiazolyl. Both aryl and heteroaryl groups may be optionally substituted. For example, M and M' can be selected from the non-limiting group consisting of optionally substituted phenyl, oxazole, and thiazole. In the Formulas herein, M and M' can be independently selected from the list of biodegradable groups above. Unless otherwise specified, aryl or heteroaryl groups described herein refers to both unsubstituted and substituted groups, i.e., optionally substituted aryl or heteroaryl groups. Alkyl, alkenyl, and cyclyl (e.g., carbocyclyl and heterocyclyl) groups may be optionally substituted unless otherwise specified. Optional substituents may be selected from the group consisting of, but are not limited to, a halogen atom (e.g., a chloride, bromide, fluoride, or iodide group), a carboxylic acid (e.g., C(O)OH), an alcohol (e.g., a hydroxyl, OH), an ester (e.g., C(O)OR OC(O)R), an aldehyde (e.g., C(O)H), a carbonyl (e.g., C(O)R, alternatively represented by C=O), an acyl halide (e.g., C(O)X, in which X is a halide selected from bromide, fluoride, chloride, and iodide), a carbonate (e.g., OC(O)OR), an alkoxy (e.g., OR), an acetal (e.g., C(OR)2R"", in which each OR are alkoxy groups that can be the same or different and R"" is an alkyl or alkenyl group), a phosphate (e.g., P(O)₄ ^3-), a thiol (e.g., SH), a sulfoxide (e.g., S(O)R), a sulfinic acid (e.g., S(O)OH), a sulfonic acid (e.g., S(O)₂OH), a thial (e.g., C(S)H), a sulfate (e.g., S(O)₄ ^2-), a sulfonyl (e.g., S(O)₂ ), an amide (e.g., C(O)NR₂, or N(R)C(O)R), an azido (e.g., N₃), a nitro (e.g., NO₂), a cyano (e.g., CN), an isocyano (e.g., NC), an acyloxy (e.g., OC(O)R), an amino (e.g., NR₂, NRH, or NH₂), a carbamoyl (e.g., OC(O)NR₂, OC(O)NRH, or OC(O)NH₂), a sulfonamide (e.g., S(O)₂NR₂, S(O)₂NRH, S(O)₂NH₂, N(R)S(O)₂R, N(H)S(O)₂R, N(R)S(O)₂H, or N(H)S(O)₂H), an alkyl group, an alkenyl group, and a cyclyl (e.g., carbocyclyl or heterocyclyl) group. In any of the preceding, R is an alkyl or alkenyl group, as defined herein. In some embodiments, the substituent groups themselves may be further substituted with, for example, one, two, three, four, five, or six substituents as defined herein. For example, a C_1-6 alkyl group may be further substituted with one, two, three, four, five, or six substituents as described herein. Compounds of the disclosure that contain nitrogens can be converted to N- oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N →O or N+-O-). Furthermore, in other instances, the nitrogens in the compounds of the disclosure can be converted to N- hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives. Working Examples The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods claimed herein are performed, made, and evaluated, and are intended to be purely exemplary described herein and are not intended to limit the scope of what the inventors regards as their disclosure. Example 1. Generation, screening, and selection of anti-CD28 antibody constructs Objectives CD28 is a key costimulatory receptor expressed on T cells, which positively contributes to T cell activation and differentiation by increasing the overall signal strength of the T cell receptor (TCR) signaling complex. In the absence of CD28 signaling, activated naïve T cells often adopt a tolerogenic state. The therapeutic hypothesis is based upon depriving T cells of CD28 co-stimulation (known as Signal 2 in the three-signal model of T cell activation) to inhibit their ability to become activated, proliferate, and gain effector functions (e.g., cytokine production such as IFNγ, and cytotoxic effector expression such as perforin and Granzyme B). The importance of CD28 in regulating T cell activation is highlighted by the presence of an endogenous competitive inhibitory receptor, CTLA4, which is induced upon T cell activation, vies for the same B7-family ligands, and delivers an inhibitory signal to the T cell to help downmodulate immune responses. It is important that the blocking reagent does not agonize CD28 signaling by engagement, to avoid a potential for exacerbating T cell activation, as was observed previously with the CD28 superagonist antibody TGN1412. This example describes a series of experiments that were undertaken in order to generate antagonistic anti-CD28 antibodies, which were found to be capable of suppressing T cell activity. Accordingly, the antibodies described in this example can be used to inhibit inappropriate T cell-mediated immune reactions and, thus, can be applied toward the treatment of the variety of immunological diseases described herein. Background T cell activation by antigen-presenting cells (e.g., myeloid and dendritic cells) is a highly regulated process that is mediated by a number of co-stimulatory and co- inhibitory receptor-ligand pairs. Three signals are considered to be important for T cell activation. Signal 1 is mediated by the TCR-MHC-antigenic peptide complex, Signal 2 is a costimulatory receptor signal (i.e., CD28), and Signal 3 is typically provided by a soluble cytokine. CD28 plays an important role in stimulating T cell activation through engagement by B7-family ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APCs). CD28 signals can induce IL-2 production and proliferation, while stabilizing anti-apoptotic BCL-XL to prevent CD95-induced apoptosis and promote T cell survival. CD28 is expressed constitutively on essentially all T cell subsets. Reagents that block CD28 engagement and signaling can prevent T cell activation, proliferation/survival, and acquisition of effector functions. The degree of T cell activation is fine-tuned by induction of CTLA-4, an inhibitory receptor that competes with CD28 for binding to CD80 and CD86 on antigen-presenting cells. CTLA4 has a higher avidity for CD80/CD86 than CD28, enabling it to out- compete CD28 for engagement, and sending an inhibitory signal. This creates a regulatory negative feedback loop to downmodulate T cell activation. The experiments that were utilized in this investigation to identify new antagonistic CD28 antibodies are described in the sections that follow. Methods Expression and purification of proteins Proteins were transiently expressed by co-transfecting separate plasmids into ExpiCHO-S™ Cells (Thermo Fisher Scientific) that express the appropriate heavy and light chain genes for heavy and light chain antibodies. Single plasmids encoding anti- CD28 sdAbs fused to indicated half-life extension molecules were on single plasmids. The anti-CD28 fusion molecules were transiently expressed in ExpiCHO cells using the EpxiFectamine CHO (Thermo Fisher Scientific) transfection reagents. The ExpiCHO-S cells were cultured in ExpiCHO expression medium (Thermo Fisher Scientific) in a shaker incubator set at 125 rpm, 37 ° C and 8% CO₂. The day prior to transfection, ExpiCHO-S cells were seeded at 3 x 10⁶ cells per ml in 30 ml of ExpiCHO Expression medium. On the day of transfection cells were split using pre-warmed (37 ° C) ExpiCHO expression media to a density of 6 x 10⁶ cells per ml. Using the manufacturer’s recommended protocol, a total 20ug of a single plasmid or equimolar amounts of two plasmids when required and 72 µL of ExpiFectamine CHO reagent were mixed in 2.4 ml of cold Opti-PRO SFM (Thermo Fisher Scientific), after incubating the mixture for 2 minutes it was then slowly added to the cells. One day (~20h) post-transfection, 7.2 ml of ExpiCHO Feed and 180 µl of ExpiCHO Enhancer were added to the ExpiFectamine- transfected cultures. Culture supernatants were harvested when cell viability dropped below 60% (~day 8), clarified by centrifugation at 3,000 rpm for 30 min and filtered using a 0.2 μm filter (Thermo Fisher Scientific). Molecule Expression and purification of CD28 proteins The following molecules were expressed, huCD28-(llama)-hinge-IgG1b-Fc, huCD28-(llama)-hinge-IgG2c-Fc, huCD28-TEV-hinge-IgGFc, huCD28(NCBI NP_006130). For use as negative controls, llama IgG1b-Fc and llama IgG2c-Fc were also expressed. Purification of CD28 proteins from ExpiCHO media Expi-CHO media (75 ml) containing expressed huCD28-huFc was incubated with 1 mL Mab select resin (Cytivia, MA), in three batches of 25 mL each, with gentle shaking for 1 h at room temperature. The resin (1 mL) is loaded and washed in a column with PBS. Next was added 1 mL of TEV protease (T4455, Sigma, MO) reaction mix in 25 mM Tris-HCl, pH 8.0, 50 mM NaCl, and the mix incubated overnight (12-20h). The cleaved CD28 is eluted from the column with Tris-HCl, pH 8.0, 50 mM NaCl, and incubated with 1 mM TCEP for 1 h, then the solution adjusted to 3.3 mM idoacetimide- biotin (EZ-Link™ Iodoacetyl-PEG2-Biotin, Thermofisher) for 1 h. The protein was then chromatographed on a Superdex-200 HiLoad gel filtration column (Cytivia, MA) eluted with PBS pH 7.2. Fractions containing monovalent biotinylated-CD28 as determined by SDS PAGE, were pooled and concentrated to 0.5 mg/ml. Typical recovery from 7 mg of Fc fusion protein was 1.4 mg of biotinylated CD28 based on concentrations determined by using the calculated A280 for each protein. Immunization of llamas Llamas were immunized with IM injections of mRNA using a schedule identical to that used for protein immunization (Baral et al.2013)to four days prior to a production bleed. PBMCs were prepared using previously described methods (Disis et al.2006; Su et al.2016). PBMCs were separated using Histopaque (1.103 g/ml) and subsequently following the protocol as described in Disis et al.2006. Antibody Selection Antibodies were identified using Phage particles were constructed a CD28 protein immunized llama PBMCs using the protocols detailed in (Pardon et al.2014). This library was selected against recombinant biotinylated monomeric human CD28 fragment in solution as described in expression and purification of proteins. Alternatively, antibodies were identified using a FACS to identify B-cells of interest from immunized llama PBMCs using the methods described (Starkie et al. 2016) . Several B-cells were FACS sorted into 96 well plates. Sorted cells were selected using the following reagents fluorescently labeled anti-llama-IgG (Genescript), anti-llama-Vhh secondary antibodies (Genescript), biotinylated huCD28 and anti-Biotin (Genscript) to FACS select for B-cells expressing anti-CD28 monoclonals. B-cells were cultured for eight days with appropriate cytokines and supernatants evaluated for binding antibodies in ELISAs and/or FACS on Jurkat cells. Wells containing positive binders were subject to PCR (Pardon et al.2014) and expressed as described above. Antibody screening ultimately led to the identification of two types of candidates that shared high affinity for CD28 and good stability as recombinant proteins: single- domain antibodies and full-length antibodies/Fab fragments. The antibodies that were identified from this study as exhibiting high affinity for CD28 are summarized in Table 9, below. Table 9. Antibodies and antibody fragments identified as having high affinity for CD28

Purification of single-domain antibodies Expressed single-domain antibodies with a 6x His C-terminal tag were purified from ExpiCHO media by capture on TALON (TAKRA) cobalt immobilized metal affinity chromatography (IMAC) resin. Resin was prewashed in 50 mM sodium phosphate buffer pH 7.4 (wash buffer) with 15x the volume of resin, then centrifuged for 2 min at 700 x g to pellet the resin. The supernatant discarded and the resin wash repeated. To the filtered media containing the expressed protein was added 3 mL of IMAC resin, then allowed to bind overnight with gentle shaking. The media resin mixture was gravity loaded into a 25 ml column. Columns containing IMAC resin were then washed with 10 column volumes (~30 ml) of wash buffer (PBS pH 7.4 (Life Tech cat# 10010-023), 2 mM imidazole) then 2x with 10ml of wash buffer. Protein was then eluted using a total of 7.5 mL 150mM imidazole /PBS pH 7 in three 2.5 mL aliquots. Proteins were then dialyzed exhaustively using Slide-A-Lyzer® 10 or 3K as appropriate (Dialysis cassette, Pierce) versus 1 x PBS (100mM NaPO₄ pH 6.8, 200mM NaCl). Protein characterization SDS PAGE was run on each sample using NuPAGE Bis-Tris 4-12% gradient gels using a MES running buffer (Thermo Fisher Scientific). Samples were prepared with either reducing or nonreducing sample buffer and briefly heated to 95 ° C. To samples electrophoresed in nonreducing buffer, N-ethyl maleimide was added to cap any free thiols and prevent unwanted disulfide scrambling as the samples cooled. Molecular weight standards (Blue Plus protein, Thermo Fisher Scientific) were included on the SDS-PAGE. Non-denaturing protein electrophoresis was performed running 1 μg of each purified protein sample; reducing conditions were performed mixing each purified sample with 10 μl of Sample Reducing Agent (Invitrogen, Carlsbad, CA) and heating at 70°C for 10 min before electrophoresis on NuPAGE 4-12% Bis-Tris Mini Gels 1.0 mm (Invitrogen, Carlsbad, CA). The bands were visualized by SimplyBlue™ SafeStain (Invitrogen, Carlsbad, CA) staining, and the gel was dried using DryEase Mini-Gel Drying System (Invitrogen, Carlsbad, CA). All procedures were performed according to the manufacturer’s instructions. Analysis of native molecule homogeneity and determination of molecular weight was done using Size Exclusion Chromatography with Light Scattering (SEC-LS) when indicated. Size exclusion chromatography (SEC) was carried out on a Zenix SEC 300 4.6 x 300 mm (Sepax Technologies) in 20 mM sodium phosphate pH 7.2, 150 mM NaCl (PBS), 0.05% NaAzide at a flow rate of 0.35ml/min using an Agilent 1260 UPLC. In addition to UV detection, the eluent was monitored with a refractive index detector (Waters, Milford, MA). Light scattering was monitored using a Wyatt Dawn 18 angle, coupled with an Optrex refractometer. Intact mass of molecules was determined mass spectrometry (Merrigen, Lowell MA). Biacore analysis of molecular binding affinities SPR binding studies were performed using a Biacore 3000 instrument (Biacore Inc., Piscataway, NJ). The target molecule was immobilized on CM5 sensorchips using the Biacore amine coupling kit according to manufacturer’s instructions. Briefly, the chip was activated with a 50 µL injection of 1:1 N-hydroxsuccinimide (NHS): 1-Ethyl-3(3- dimethylaminopropyl)-carbodiimide hydrochloride (EDC). A 50 µL sample of antibody, diluted to 50 µg/ml in 10 mM sodium acetate, pH 5.0 was injected over one quadrant of the activated chip. A second quadrant was exposed to 10 mM sodium acetate, pH 5.0 as a control surface. Excess free amine groups were capped with a 50 µL injection of 1 M Ethanolamine. Surfaces were conditioned with 5 x 30 µL injections of 10 mM NaH₂PO₄. Typical immobilization levels were 5000 RU. All samples were prepared in Biacore buffer (10 mM HEPES pH 7, 150 mM NaCl, 3.4 mM EDTA, 0.005% p-20 detergent, 0.1% BSA). This same buffer was used as the running buffer during sample analysis. For immobilizations, the same Biacore buffer without BSA was used as the running buffer. FACS Assays and Analysis K_D values were determined as follows in binding assays to the Jurkat cell line E6.1 (TB152 ATCC) expressing human CD28 and compared with 293 cells as a negative control. 1x10⁶ cells/ml in FACS buffer (PBS, 5% FBS) were incubated with appropriately serially diluted antibody on ice for 1h. Next cells were washed three times with FACS buffer, the resuspended in FACS buffer containing the appropriate secondary antibody. Secondary antibodies used included steptavidin phycoerythrin for biotinylated antibodies, for His tagged proteins the secondary used was anti-His-FITC (GenScript, NJ) at 0.5 µg/mL, or anti-hFc phycoerythrin labeled secondary (Molecular Probes, Eugene, OR) for any Fc containing constructs. Cells were incubated with the secondary antibody for an additional 0.5-1h at 4C and washed 3x with FACS buffer and resuspended in 100µL of FACS buffer. The fluorescent staining of the cellular bound antibody on the cells was quantified by determining the mean channel fluorescence by FACS. Cellular fluorescence was determined on FACScan equipped with Cellquest software (Becton-Dickinson, Franklin Lakes, NJ). The data were plotted as a function of mean channel fluorescence versus the concentration of the receptor. K_D and IC₅₀ values were determined from the half-maximal values of 4-parameter fits of the data using Delta Graph (Red Rock Software, Salt Lake City, UT) or GraphPad Prism (San Diego, CA). Humanization Antibody humanization was done using the general methods CDR grafting (Hanf et al.2014). The method involves grafting the mature llama CDR sequences onto a germline human acceptor framework with high homology to the parent sequence. Structural defects due to sequence mismatches at the graft interface were fixed by mutating some framework residues to llama, or by mutating some residues on the CDRs’ backside to llama. The triad of llama amino acids that impart heavy chain solubility and prevent the need for light chain pairing are not mutated (Muyldermans et al.1994). One of the antibodies identified from the llama single-domain library, II-A, was advanced as a putative candidate because of its particularly advantageous properties, including its small size (~13 kDa) and observed stability and binding affinity to recombinant CD28-Fc protein. V_H single-domain antibodies (VHH antibodies, also referred to herein as sdAbs), as well as human serum albumin (HSA)/mouse serum albumin (MSA) conjugates thereof, were generated as recombinant proteins to further characterize II-A. These experiments are described in further detail in the examples that follow.

Assessment of Receptor Occupancy Assessment of CD28 receptor occupancy (RO) in mice and non-human primates (NHP) was performed using the direct RO assays. For in vivo NHP studies, samples were divided into two 100-ml aliquots; to one aliquot, a saturating I-A-HSA concentration was added, and both samples were incubated at 37°C for 1 hour. Blood samples were then washed three times with 2 ml of FACS buffer (0.5% fetal bovine serum and 0.1% sodium azide in PBS), placed on ice, and incubated with Human TruStain FcX™ (Biolegend, San Diego, CA) for 15 minutes to block Fc mediated nonspecific binding. A rabbit anti-CD28-I-A polyclonal Ab was added and incubated for 30 minutes at 4°C and shaken well. Samples were washed once with 2 ml of FACS buffer, decanted, and stained with anti-cyno CD3 APC-Cy7, anti-CD4 FITC, anti-CD45 PerCP, and anti-CD8 BV510 (BD Biosciences, San Jose, CA) along with Alexa Fluor 647-conjugated Donkey anti-rabbit IgG (Biolegend, San Diego, CA). A background sample was generated by staining a control group or baseline (pre-bleed) sample with all assay reagents in the absence of I-A-HSA. Samples were further incubated for 30 minutes on ice protected from light. Blood samples were then washed once with 2 ml of FACS buffer, and 2.5 ml of FACS Lysing Solution (BD Biosciences) was added for 15 minutes to lyse red blood cells and fix samples. After centrifugation and decanting, samples were resuspended in 200 ul of FACS Lysing Solution for flow cytometry analysis (BD FACS Canto II). For the CD28 RO in hCD28ki mice, the experimental procedure was similar to what was described above, except that saturating I-A-MSA concentration was added, and anti-mouse CD3 PE-Cy7, anti-CD4 FITC and anti-CD8 BV510 (Biolegend, San Diego, CA) was used to identify mouse T cell population. A blank mouse blood sample was used to determine the maximum occupancy in the absence of I-A-MSA. In addition, a background control sample was generated by using the Alexa Fluor 647-conjugated Donkey anti-rabbit IgG (Biolegend, San Diego, CA) in absence of anti-CD28 I-A-MSA. All flow cytometry data were analyzed using FACSDiva software (BD Biosciences). The percentage of the CD28 RO for the direct RO assay was calculated as follows: ^{Receptor Occupancy:}

Assessment of T-cell Dependent Antibody Response To evaluate the KLH-induced T-cell-dependent antibody response (TDAR), three groups of female hCD28ki mice (N=5 per dose group, 20–25 g) received intravenous injections of PBS, 0.25 mg/kg LNP-1A containing MSA, 0.25 mg/kg LNP-1A containing I-A-MSA, or 0.1 mg/kg LNP-1A containing I-A-MSA twice weekly for three weeks. Twenty-four hours after the first dose, mice were immunized with 12.5 mg/kg KLH in PBS via intraperitoneal injections, and repeatedly injected KLH at day 15. Blood samples were collected from which whole blood CD28 RO was determined at day 9, day 14 and day 21. In addition, serum samples were harvested and analyzed for anti- KLH IgG on day 14 and day 21 post the KLH challenge. To evaluate KLH-induced TDAR in monkey, four groups of monkeys (N=6 females, 2.7–4.5 kg) were given by once weekly by 60 minutes intravenous infusion of PBS or 0.2, 0.5 and 1.5 mg/kg LNP-1B LNP containing I-A-HSA for 3 weeks (Days 0, 7, and 14). All monkeys were immunized with KLH 24 hours after the day 0 dosing of the I-A-HSA. Serial blood samples were collected into K2EDTA tubes at predose, 24 and 96, 168, 192, 264, 336, 360, 432, and 672 hours post dose. Plasma samples were then harvested and stored at -80°C until further analysis for drug concentrations. In addition, whole blood samples were collected at various time points for the CD28 RO analysis. Example 2. CD28 binding and pharmacokinetic properties of an exemplary anti- CD28 antibody CD28 affinity, T cell IL-2 suppression, and T cell proliferation To assess the interaction between CD28 and antibody candidate II-A, CHO cells were transfected with a plasmid encoding a II-A/HSA fusion construct. The purified protein was subsequently used to determine the binding affinity to human T cells in vitro. These experiments resulted in a calculated K_D of 10.6 nM. Additionally, the EC₅₀ value for inhibiting T cell IL-2 production in response to CD80-transfected 293T cells plus phytohaemagglutinin (polyclonal TCR stimulation lectin) was calculated to be approximately 2.6 nM, and in a mixed human lymphocyte reaction (MLR), II-A was determined to exhibit an EC₅₀ of 58.1 nM for inhibiting T cell proliferation. A comprehensive list of EC₅₀ values is listed in Table 10. Table 10. EC₅₀ of anti-CD28 antagonists inhibit human primary T cell IL-2 production in response to CD80-transfected 293T cells plus polyclonal TCR stimulation lectin.

Pharmacokinetic and pharmacodynamic properties of II-A To assess the plasma protein levels and receptor occupancy of II-A, hCD28 knock-in mice were intravenously injected with 0.25 mg/kg lipid nanoparticles (LNP) containing either aCD28-His or aCD28-MSA mRNA. Plasma aCD28-MSA levels peaked at approximately 1000 nM 24 hours post-injection, indicating that the MSA moiety improved in vivo plasma protein levels of the antibody. CD8+ T cells exhibited higher receptor occupancy (RO) of the aCD28-MSA antibody than CD4+ T cells beginning at 10 hours post-injection. CD4+ T cell RO of the aCD28-MSA antibody peaked around 40% 24 hours post-injection, after which the RO decreased to between 20-40% by 72 hours post-injection. CD8+ T cell RO of the aCD28-MSA antibody peaked around 50% 24 hours post-injection, after which the RO decreased to between 20-40% by 72 hours post-injection. For both CD4+ T cells and CD8+ T cells, RO of the aCD28-His antibody remained below 20%, indicating that the MSA moiety improved in vivo receptor occupancy in CD4+ T cells and CD8+ T cells (data not shown). To evaluate the half-life of the antibody, BALB/c mice were intravenously injected with 0.5 mg/kg LNP-1A containing the MSA moiety, 0.5 mg/kg LNP-1A containing aCD28-MSA mRNA, or 5 mg/kg aCD28-MSA protein. Serum was collected up to 220 hours post-injection and diluted 1:800 fold prior to incubating on ELISA plates coated with human/cyno CD28-hFc at 1µg/mL. Protein concentration of CD28 was determined by ELISA. V5 tagged aCD28 was detected by anti-V5-HRP antibody, and a standard curve was generated. The half-life was then estimated using log concentration regression in Prism. The half-life of aCD28-MSA was 46.7 hours post-injection of aCD28-MSA and 47.8 hours post-injection of LNP-1A containing aCD28-MSA mRNA (data not shown). A comprehensive list of binding affinities is listed in Table 11. Table 11. Binding kinetics of anti-CD28 II-A humanization variants against human CD28-His on a Biacore.

Example 3. Inhibition of cytokine release in vitro by II-A To assess the ability of II-A to inhibit cytokine release in vitro, two donor lots of human T cells were treated with 0, 0.1, 1, or 10 µg/mL anti-CD28 II-A -HSA in combination with anti-CD3 stimulation. The II-A-HSA antibody treatment did not induce IL-2 or IFNy release from human T cells in vitro. To assess whether crosslinking anti- CD28 superagonist ANC28.1 to the II-A-HSA antibody would stimulate cytokine release on human T cells, two donor lots of human T cells were treated with 0, 5.6, 16.7, or 50 µg/mL murine IgG, anti-CD28 II-A-HSA, or crosslinked ANC28.1 and II-A-HSA. Intentional crosslinking did not induce IL-2 or IL-10 release from human T cells in vitro (data not shown). Example 4. Mice treated with intravenous administration of LNP containing II-A- MSA mRNA were protected from graft versus host disease (GVHD). To assess the protective effects of II-A in the context of GVHD, NOD-scid IL2Ry^null (NSG) mice were treated with intravenous injections of PBS, 0.25 mg/kg LNP- 1A containing MSA mRNA, 0.25 mg/kg LNP-1A containing aCD28-MSA mRNA, or 5 mg/kg aCD28-MSA peptides twice weekly for four weeks (FIG.1). While naïve, PBS, and LNP-1A containing MSA mRNA mice experienced reductions in body weight, the mice treated with aCD28-MSA peptides and LNP-1A containing aCD28-MSA mRNA maintained body weight (FIG.1A). Likewise, serum alanine aminotransferase levels of the aCD28-MSA treatment groups were decreased compared to the PBS and MSA groups (FIG.1B). The serum aCD28-MSA levels were highest in the group that received intravenous administration of LNP-1A containing aCD28-MSA mRNA (data not shown). Of all of the treatment groups, only LNP-1A containing aCD28-MSA mRNA reduced liver engraftment by human CD4+ (data not shown), CD8+ (data not shown), and CD45+ T (FIG.2C) cells in NSG mice. Additionally, NSG mice treated twice weekly with LNP-1A containing aCD28-MSA mRNA exhibited significantly fewer activated CD4+ T cells (data not shown) and CD8+ T cells, as shown by the reduction in effector molecules PDL1 and granzyme B compared to the other treatment groups (FIG.3). Example 5. Mice treated with intravenous administration of LNP containing I-A- MSA RNA were protected from keyhole limpet hemocyanin (KLH)-stimulated T- cell dependent antibody response (TDAR). To assess the protective effects of I-A in the context of TDAR (see Example 6 for additional details), hCD28ki mice (mice with knock-in human CD28 receptor) were subcutaneously treated with 12.5 mg/kg KLH on day 1 and day 15. KLH treatment stimulated T-cell dependent antibody response, which mimics inappropriate immune response in subjects (e.g., humans) with diseases (e.g., autoimmune diseases). Mice were treated with intravenous injections of PBS, 0.25 mg/kg LNP-1A containing MSA, 0.25 mg/kg LNP-1A containing I-A-MSA, or 0.1 mg/kg LNP-1A containing I-A-MSA twice weekly for three weeks (FIG.4). The mice were bled prior to the first KLH treatment, and then subsequently on day 9, day 14, and day 21 (FIG.4A). The group treated intravenously twice weekly with 0.25 mg/kg LNP-1A containing I-A-MSA exhibited higher receptor occupancy of mCD3+mCD4+ and mCD3+mCD8+ cells than the other groups (FIG.4B). The 0.25 mg/kg LNP-1A containing I-A-MSA group also exhibited the lowest anti-KLH IgG serum levels compared to the other groups by day 21 (FIG.4C). Example 6. Non-human primates treated with intravenous administration of LNP containing I-A-MSA RNA were protected from keyhole limpet hemocyanin (KLH)- stimulated T-cell dependent antibody response (TDAR). To assess KLH-induced TDAR in monkey, monkeys were given once weekly a 60 minutes intravenous infusion of PBS or 0.2, 0.5 and 1.5 mg/kg LNP-1B containing I- A-HSA for 3 weeks (Days 0, 7, and 14). All monkeys were immunized with KLH 24 hours after the day 0 dosing of the I-A-HSA as shown in FIGs.5A-D. The increases in MFI and %RO were observed on 24 hr post injection with % RO values reaching up to 64% and 62% of group mean averages for CD4+ T helper (FIG.5A) and CD8+ T cytotoxic (FIG.5B) lymphocytes, respectively, which further increased on 96 hr post injection up to 87% and 76% of group mean averages. On Day 7, receptors were occupied with %RO values which remained above the range of pretreatment and controls. Following the second dose administration, %RO values were increased on 24 and 96 hr post 2^nd injection. Percent RO values on T-helper lymphocytes (FIG.5A) trended toward recovery on Day 14 but remained increased for T-cytotoxic lymphocytes (FIG.5B). Following the third dose administration, bound receptors were increased on 24 and 96 hr post 3^rd injection. On Day 28 (336 hr post 3^rd injection), the %RO values generally trended toward pretreatment values, but receptors generally remained bound. Animals dosed with I-A-HSA at 0.2 and 0.5 mg/kg did not show a decrease in anti-KLH IgM, and IgG responses compared to the control. I-A-HSA related decreases in anti-KLH IgM (4% to 68% of concurrent control mean values) responses were observed in a majority of animals dosed with 1.5 mg/kg LNP-1B containing I-A-HSA on Days 9 through 28 (FIG.5C). Some of these decreases attained statistical significance compared to control animals. I-A-HSA related decreases anti-KLH IgG (36% to 79% of concurrent control mean values) responses were observed in all animals dosed with 1.5 mg/kg LNP-1B containing I-A-HSA on Days 9 through 28 (FIG.5D). Some of these decreases attained statistical significance compared to control animals. Intravenous fusion of LNP-1B containing I-A-HSA mRNA, results in dose dependent expression of I-A-HSA protein in vivo. The expressed protein binds cell surface CD28 receptor on CD4- and CD8-T-cells. The I-A-HSA CD28 receptor occupancy is dose dependent. At the highest dose of 1.5 mg/Kg I-A-HSA mRNA there was a commensurate decrease observed for both IgM and IgG anti-KLH titers in the NHP TDAR model. References Baral TN, MacKenzie R, Ghahroudi MA (2013) Current Protocols in Immunology. 2.17.1-2.17.57. https://doi.org/10.1002/0471142735.im0217s103 Disis ML, Rosa C dela, Goodell V, et al. (2006) Maximizing the retention of antigen specific lymphocyte function after cryopreservation. J Immunol Methods 308:13–18. https://doi.org/10.1016/j.jim.2005.09.011 Hanf KJM, Arndt JW, Chen LL, et al. (2014) Antibody humanization by redesign of complementarity-determining region residues proximate to the acceptor framework. Methods 65:68–76. https://doi.org/10.1016/j.ymeth.2013.06.024 Muyldermans S, Atarhouch T, Saldanha J, et al. (1994) Sequence and structure of V H domain from naturally occurring camel heavy chain immunoglobulins lacking light chains. Protein Eng Des Sel 7:1129–1135. https://doi.org/10.1093/protein/7.9.1129 Pardon E, Laeremans T, Triest S, et al. (2014) A general protocol for the generation of Nanobodies for structural biology. Nat Protoc 9:nprot.2014.039. https://doi.org/10.1038/nprot.2014.039 Starkie DaleO, Compson JE, Rapecki S, Lightwood DJ (2016) Generation of Recombinant Monoclonal Antibodies from Immunised Mice and Rabbits via Flow Cytometry and Sorting of Antigen-Specific IgG+ Memory B Cells. Plos One 11:e0152282. https://doi.org/10.1371/journal.pone.0152282 Su K-Y, Watanabe A, Yeh C-H, et al. (2016) Efficient Culture of Human Naive and Memory B Cells for Use as APCs. J Immunol 197:4163–4176. https://doi.org/10.4049/jimmunol.1502193 Other Embodiments In addition to the sections above, the compositions and methods of the disclosure are further captured in the following enumerated embodiments: 1. A single-domain antibody comprising the following complementarity- determining regions (CDRs): (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). 2. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GDTICGNV (SEQ ID NO: 4); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). 3. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSIFSINA (SEQ ID NO: 5); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). 4. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAGPPWWRYGGGSSWYERPREYDY (SEQ ID NO: 7). 5. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADRTGQTVQATYWEYDY (SEQ ID NO: 8). 6. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFTLDYYA (SEQ ID NO: 9); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISSSHGST (SEQ ID NO: 10); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence VVFWGPSVDMITGA (SEQ ID NO: 11). 7. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFTLDYYA (SEQ ID NO: 9); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). 8. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADLWGSSWYSAVPGNDY (SEQ ID NO: 12). 9. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GDTICISA (SEQ ID NO: 13); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGST (SEQ ID NO: 6); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3). 10. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GSVFSGNV (SEQ ID NO: 1); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ITSGGSA (SEQ ID NO: 2); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence HPLSLASSWYSS (SEQ ID NO: 14). 11. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTYSTYN (SEQ ID NO: 15); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISWTGSNT (SEQ ID NO: 16); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ATELEFYNRRWPPTLDY (SEQ ID NO: 17). 12. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTFGNYV (SEQ ID NO: 18); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IRWSDGTT (SEQ ID NO: 19); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AADVHGELFPQVQSHYDY (SEQ ID NO: 20). 13. A single-domain antibody comprising the following CDRs: (a) a CDR-1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GRTFSAYC (SEQ ID NO: 21); (b) a CDR-2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IMWSDGST (SEQ ID NO: 22); and (c) a CDR-3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAGVCDSSRLLTRKYEYGY (SEQ ID NO: 23). 14. An antibody, or antigen-binding fragment thereof, comprising the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ESVYSDNR (SEQ ID NO: 24); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence LAS (SEQ ID NO: 25); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AGFKIRGTDGHG (SEQ ID NO: 26); (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFSFHFTYW (SEQ ID NO: 27); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IHAGSTGTT (SEQ ID NO: 28); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARLDDIDDYFNL (SEQ ID NO: 29). 15. An antibody, or antigen-binding fragment thereof, comprising the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QSIYSD (SEQ ID NO: 30); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAA (SEQ ID NO: 31); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QSFHGYSGTYG (SEQ ID NO: 32); (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GLSFNVYW (SEQ ID NO: 33); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence IGPSGDGKT (SEQ ID NO: 34); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARDYTNAFDL (SEQ ID NO: 35). 16. An antibody, or antigen-binding fragment thereof, comprising the following CDRs: (a) a CDR-L1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QNIYSD (SEQ ID NO: 36); (b) a CDR-L2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence AAA (SEQ ID NO: 31); (c) a CDR-L3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence QGFHGSSGSHG (SEQ ID NO: 37); (d) a CDR-H1 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence GFSDRYW (SEQ ID NO: 38); (e) a CDR-H2 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ISAGSNAKT (SEQ ID NO: 39); and (f) a CDR-H3 having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence ARDYANYFDL (SEQ ID NO: 40). 17. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 42. 18. The antibody of embodiment 17, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 42. 19. The antibody of embodiment 18, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42. 20. The antibody of embodiment 19, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 42. 21. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 43. 22. The antibody of embodiment 21, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 43. 23. The antibody of embodiment 22, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43. 24. The antibody of embodiment 23, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 43. 25. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 44. 26. The antibody of embodiment 25, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 44. 27. The antibody of embodiment 26, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44. 28. The antibody of embodiment 27, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 44. 29. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 45. 30. The antibody of embodiment 29, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 45. 31. The antibody of embodiment 30, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 45. 32. The antibody of embodiment 31, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 45. 33. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 46. 34. The antibody of embodiment 33, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 46. 35. The antibody of embodiment 34, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46. 36. The antibody of embodiment 35, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 46. 37. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 47. 38. The antibody of embodiment 37, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 47. 39. The antibody of embodiment 38, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 47. 40. The antibody of embodiment 39, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 47. 41. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 48. 42. The antibody of embodiment 41, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 48. 43. The antibody of embodiment 42, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 48. 44. The antibody of embodiment 43, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 48. 45. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 49. 46. The antibody of embodiment 45, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 49. 47. The antibody of embodiment 46, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49. 48. The antibody of embodiment 47, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 49. 49. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 50. 50. The antibody of embodiment 49, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 50. 51. The antibody of embodiment 50, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50. 52. The antibody of embodiment 51, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 50. 53. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 51. 54. The antibody of embodiment 53, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 51. 55. The antibody of embodiment 54, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51. 56. The antibody of embodiment 55, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 51. 57. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 52. 58. The antibody of embodiment 57, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 52. 59. The antibody of embodiment 58, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52. 60. The antibody of embodiment 59, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 52. 61. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 53. 62. The antibody of embodiment 61, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 53. 63. The antibody of embodiment 62, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 53. 64. The antibody of embodiment 63, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 53. 65. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 54. 66. The antibody of embodiment 65, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 54. 67. The antibody of embodiment 66, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 54. 68. The antibody of embodiment 67, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 54. 69. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 55. 70. The antibody of embodiment 69, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 55. 71. The antibody of embodiment 70, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 55. 72. The antibody of embodiment 71, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 55. 73. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 56. 74. The antibody of embodiment 73, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 56. 75. The antibody of embodiment 74, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 56. 76. The antibody of embodiment 75, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 56. 77. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 57. 78. The antibody of embodiment 77, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 57. 79. The antibody of embodiment 78, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57. 80. The antibody of embodiment 79, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 57. 81. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 58. 82. The antibody of embodiment 81, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 58. 83. The antibody of embodiment 82, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58. 84. The antibody of embodiment 83, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 58. 85. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 59. 86. The antibody of embodiment 85, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 59. 87. The antibody of embodiment 86, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59. 88. The antibody of embodiment 87, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 59. 89. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 60. 90. The antibody of embodiment 89, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 60. 91. The antibody of embodiment 90, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60. 92. The antibody of embodiment 91, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 60. 93. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 61. 94. The antibody of embodiment 93, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 61. 95. The antibody of embodiment 94, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 61. 96. The antibody of embodiment 95, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 61. 97. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 62. 98. The antibody of embodiment 97, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 62. 99. The antibody of embodiment 98, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 62. 100. The antibody of embodiment 99, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 62. 101. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 63. 102. The antibody of embodiment 101, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 63. 103. The antibody of embodiment 102, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 63. 104. The antibody of embodiment 103, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 63. 105. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 65. 106. The antibody of embodiment 105, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 65. 107. The antibody of embodiment 106, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65. 108. The antibody of embodiment 107, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 65. 109. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 67. 110. The antibody of embodiment 109, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 67. 111. The antibody of embodiment 110, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67. 112. The antibody of embodiment 111, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 67. 113. The antibody of any one of embodiments 1-16, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 69. 114. The antibody of embodiment 113, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 69. 115. The antibody of embodiment 114, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 69. 116. The antibody of embodiment 115, wherein the antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 69. 117. The antibody of any one of embodiments 14-116, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 64. 118. The antibody of embodiment 117, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 64. 119. The antibody of embodiment 118, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 64. 120. The antibody of embodiment 119, wherein the antibody comprises a light chain variable domain having the amino acid sequence of SEQ ID NO: 64. 121. The antibody of any one of embodiments 14-116, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 66. 122. The antibody of embodiment 121, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 66. 123. The antibody of embodiment 122, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66. 124. The antibody of embodiment 123, wherein the antibody comprises a light chain variable domain having the amino acid sequence of SEQ ID NO: 66. 125. The antibody of any one of embodiments 14-116, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 68. 126. The antibody of embodiment 125, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 68. 127. The antibody of embodiment 126, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68. 128. The antibody of embodiment 127, wherein the antibody comprises a light chain variable domain having the amino acid sequence of SEQ ID NO: 68. 129. The antibody of any one of embodiments 1-128, wherein the antibody specifically binds CD28. 130. The antibody or any one of embodiments 1-129, wherein the antibody inhibits CD28 signaling. 131. The antibody of any one of embodiments 1-130, wherein the antibody binds CD28 with a K_D of no greater than 100 nM. 132. The antibody of embodiment 131, wherein the antibody binds CD28 with a K_D of from 1 nM to 100 nM. 133. The antibody of embodiment 132, wherein the antibody binds CD28 with a K_D of from 1 nM to 50 nm, optionally wherein the antibody binds CD28 with a K_D of from 1 nM to 25 nM, optionally wherein the antibody binds CD28 with a K_D of from 1 nM to 10 nM. 134. The antibody of any one of embodiments 1-133, wherein the antibody binds CD28 with a k_on of from 10³ M^-1s^-1 to 10⁵ M^-1s^-1. 135. The antibody of any one of embodiments 1-134, wherein the antibody binds CD28 with a k_off of from 10^-4 s^-1 to about 10^-5 s^-1. 136. The antibody of any one of embodiments 1-135, wherein the antibody reduces expression of one or more proteins selected from CTLA-4, CD80, CD86, CD95, YMNM, PI3K, PIP3, AKT, IL2, mTOR, and BCL-XL in a CD28-expressing T cell. 137. The antibody of any one of embodiments 1-136, wherein the antibody inhibits GrB activation in a CD28-expressing T cell. 138. The antibody of any one of embodiments 1-137, wherein the antibody inhibits PD-1 activation in a CD28-expressing T cell. 139. The antibody of any one of embodiments 1-138, wherein the antibody reduces proliferation and/or activity of CD4+ T cells in a subject, optionally wherein the CD4+ T cells are autoreactive T cells. 140. The antibody of any one of embodiments 1-139, wherein the antibody reduces proliferation and/or activity of CD8+ T cells in a subject, optionally wherein the CD8+ T cells are autoreactive T cells. 141. The antibody of any one of embodiments 14-140, wherein the antibody is a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual- variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a domain antibody, a Fv fragment, a Fab fragment, a F(ab’)₂ molecule, or a tandem scFv (taFv). 142. A nucleic acid encoding the antibody of any one of embodiments 1-141. 143. The nucleic acid of embodiment 142, wherein the nucleic acid is an mRNA. 144. The nucleic acid of embodiment 142 or 143, wherein the nucleic acid comprises, in the 5’-to-3’ direction: (a) a 5’ cap structure; (b) a 5’ untranslated region (UTR); (c) an open reading frame encoding the antibody, wherein the open reading frame consists of nucleosides selected from the group consisting of (i) uridine or a modified uridine, (ii) cytidine or a modified cytidine, (iii) adenosine or a modified adenosine, and (iv) guanosine or a modified guanosine; (d) a 3’ UTR; and (e) a 3’ tailing sequence of linked nucleosides. 145. The nucleic acid of embodiment 144, wherein the open reading frame of nucleosides selected from the group consisting of (i) a modified uridine, (ii) cytidine, (iii) adenosine, and (iv) guanosine. 146. The nucleic acid of embodiment 144 or 145, wherein the modified uridine is 1- methylpseudouridine, pseudouridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza- uridine, 2-thio-5-aza-uridine, 2-thio-uridine, 4-thio-uridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxy-uridine, 5-aminoallyl-uridine, 5-halo-uridine, 3-methyl-uridine, 5-methoxy-uridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5- carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl- uridine, 5-carboxyhydroxymethyl-uridine methyl ester, 5-methoxycarbonylmethyl- uridine, 5-methoxycarbonylmethyl-2-thio-uridine, 5-aminomethyl-2-thio-uridine, 5- methylaminomethyl-uridine, 5-methylaminomethyl-2-thio-uridine, 5-methylaminomethyl- 2-seleno-uridine, 5-carbamoylmethyl-uridine, 5-carboxymethylaminomethyl-uridine, 5- carboxymethylaminomethyl-2-thio-uridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine, 5-methyl-2-thio-uridine, 1- methyl-4-thio-pseudouridine, 4-thio-1-methyl-pseudouridine, 3-methylpseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza- pseudouridine, dihydrouridine, dihydropseudouridine, 5,6-dihydrouridine, 5-methyl- dihydrouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2- methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1- methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine, 5-(isopentenylaminomethyl)uridine, 5- (isopentenylaminomethyl)-2-thio-uridine, α-thio-uridine, 2′-O-methyl-uridine, 5,2′-O- dimethyl-uridine, 2′-O-methyl-pseudouridine, 2-thio-2′-O-methyl-uridine, 5- methoxycarbonylmethyl-2′-O-methyl-uridine, 5-carbamoylmethyl-2′-O-methyl-uridine, 5- carboxymethylaminomethyl-2′-O-methyl-uridine, 3,2′-O-dimethyl-uridine, 5- (isopentenylaminomethyl)-2′-O-methyl-uridine, 1-thio-uridine, deoxythymidine, 2’-F-ara- uridine, 2’-F-uridine, 2’-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, or 5-[3-(1-E- propenylamino)uridine. 147. The nucleic acid of embodiment 146, wherein the modified uridine is 1- methylpseudouridine. 148. The nucleic acid of any one of embodiments 144, 146, and 147, wherein the modified cytidine is 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetyl-cytidine, 5-formyl-cytidine, N4-methyl-cytidine, 5-methyl-cytidine, 5-halo- cytidine, 5-hydroxymethyl-cytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo- pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4- thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl- 1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2- thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4- methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, lysidine, α-thio- cytidine, 2′-O-methyl-cytidine, 5,2′-O-dimethyl-cytidine, N4-acetyl-2′-O-methyl-cytidine, N4,2′-O-dimethyl-cytidine, 5-formyl-2′-O-methyl-cytidine, N4,N4,2′-O-trimethyl-cytidine, 1-thio-cytidine, 2’-F-ara-cytidine, 2’-F-cytidine, or 2’-OH-ara-cytidine. 149. The nucleic acid of any one of embodiments 144 and 146-148, wherein the modified adenosine is 2-amino-purine, 2, 6-diaminopurine, 2-amino-6-halo-purine, 6- halo-purine, 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenine, 7-deaza-8- aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2,6- diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine, 2-methyl- adenine, N6-methyl-adenosine, 2-methylthio-N6-methyl-adenosine, N6-isopentenyl- adenosine, 2-methylthio-N6-isopentenyl-adenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, N6-glycinylcarbamoyl-adenosine, N6-threonylcarbamoyl-adenosine, N6-methyl-N6- threonylcarbamoyl-adenosine, 2-methylthio-N6-threonylcarbamoyl-adenosine, N6,N6- dimethyl-adenosine, N6-hydroxynorvalylcarbamoyl-adenosine, 2-methylthio-N6- hydroxynorvalylcarbamoyl-adenosine, N6-acetyl-adenosine, 7-methyl-adenine, 2- methylthio-adenine, 2-methoxy-adenine, α-thio-adenosine, 2′-O-methyl-adenosine, N6,2′-O-dimethyl-adenosine, N6,N6,2′-O-trimethyl-adenosine, 1,2′-O-dimethyl- adenosine, 2′-O-ribosyladenosine, 2-amino-N6-methyl-purine, 1-thio-adenosine, 8- azido-adenosine, 2’-F-ara-adenosine, 2’-F-adenosine, 2’-OH-ara-adenosine, or N6-(19- amino-pentaoxanonadecyl)-adenosine. 150. The nucleic acid of any one of embodiments 144 and 146-149, wherein the modified guanosine is inosine, 1-methyl-inosine, wyosine, methylwyosine, 4-demethyl- wyosine, isowyosine, wybutosine, peroxywybutosine, hydroxywybutosine, 7-deaza- guanosine, queuosine, epoxyqueuosine, galactosyl-queuosine, mannosyl-queuosine, 7- cyano-7-deaza-guanosine, 7-aminomethyl-7-deaza-guanosine, archaeosine, 7-deaza-8- aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza- guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6- methoxy-guanosine, 1-methyl-guanosine, N2-methyl-guanosine, N2,N2-dimethyl- guanosine, N2,7-dimethyl-guanosine, N2, N2,7-dimethyl-guanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, α-thio-guanosine, 2′-O-methyl-guanosine, N2-methyl- 2′-O-methyl-guanosine, N2,N2-dimethyl-2′-O-methyl-guanosine, 1-methyl-2′-O-methyl- guanosine, N2,7-dimethyl-2′-O-methyl-guanosine, 2′-O-methyl-inosine, 1,2′-O-dimethyl- inosine, 2′-O-ribosylguanosine, 1-thio-guanosine, O6-methyl-guanosine, 2’-F-ara- guanosine, or 2’-F-guanosine. 151. The nucleic acid of any one of embodiments 144-150, wherein the 3’ tailing sequence of linked nucleosides is a poly-adenylate (polyA) tail or a polyA-G quartet. 152. The nucleic acid of embodiment 151, wherein the 3’ tailing sequence of linked nucleosides is a polyA tail. 153. The nucleic acid of embodiment 152, wherein the polyA tail comprises from 100 to 200 contiguous adenosine residues. 154. The nucleic acid of embodiment 153, wherein the polyA tail comprises about 160 contiguous adenosine residues. 155. The nucleic acid of any one of embodiments 144-154, wherein the 5’ cap structure is Cap0, Cap1, ARCA, inosine, 1-methyl-guanosine, 2′fluoroguanosine, 7- deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, or 2- azidoguanosine. 156. A pharmaceutical composition comprising the antibody of any of embodiments 1-141 or the nucleic acid of any one of embodiments 142-155. 157. The pharmaceutical composition of embodiment 156, further comprising one or more pharmaceutically acceptable carriers, diluents, and/or excipients. 158. The pharmaceutical composition of embodiment 156 or 157, wherein the pharmaceutical composition comprises the antibody of any one of embodiments 1-141. 159. The pharmaceutical composition of embodiment 156 or 157, wherein the pharmaceutical composition comprises the nucleic acid of any one of embodiments 141-155. 160. The pharmaceutical composition of any one of embodiments 156-159, wherein the pharmaceutical composition comprises a plurality of lipid nanoparticles encapsulating the antibody or nucleic acid. 161. The pharmaceutical composition of embodiment 160, wherein the plurality of lipid nanoparticles has a mean particle size of from 80 nm to 160 nm. 162. The pharmaceutical composition of embodiment 160 or 161, wherein the plurality of lipid nanoparticles has a polydispersity index (PDI) of from 0.02 to 0.2. 163. The pharmaceutical composition of any one of embodiments 160-162, wherein the plurality of lipid nanoparticles has a lipid:nucleic acid ratio of from 10 to 20. 164. The pharmaceutical composition of any one of embodiments 160-163, wherein the lipid nanoparticles comprise a neutral lipid, an ionizable cationic lipid, a polyethyleneglycol (PEG) lipid, and/or a sterol. 165. The pharmaceutical composition of embodiment 164, wherein the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine. 166. The pharmaceutical composition of embodiment 164 or 165, wherein the ionizable cationic lipid is selected from:

, or N-oxides, salts, or isomers thereof. 167. The pharmaceutical composition of any one of embodiments 164-166, wherein the PEG lipid is PEG 2000 dimyristoyl glycerol. 168. The pharmaceutical composition of any one of embodiments 164-167, wherein the sterol is cholesterol, adosterol, agosterol A, atheronals, avenasterol, azacosterol, blazein, cerevisterol, colestolone, cycloartenol, daucosterol, 7- dehydrocholesterol, 5-dehydroepisterol, 7-dehydrositosterol, 20α,22R- dihydroxycholesterol, dinosterol, epibrassicasterol, episterol, ergosterol, ergosterol, fecosterol, fucosterol, fungisterol, ganoderenic acid, ganoderic acid, ganoderiol, ganodermadiol, 7α-hydroxycholesterol, 22R-hydroxycholesterol, 27-hydroxycholesterol, inotodiol, lanosterol, lathosterol, lichesterol, lucidadiol, lumisterol, oxycholesterol, oxysterol, parkeol, saringosterol, spinasterol, sterol ester, trametenolic acid, zhankuic acid, or zymosterol. 169. The pharmaceutical composition of embodiment 168, wherein the sterol is cholesterol. 170. A host cell comprising the antibody of any one of embodiments 1-141 or the nucleic acid of any one of embodiments 142-155. 171. The host cell of embodiment 170, wherein the host cell is a prokaryotic cell. 172. The host cell of embodiment 170, wherein the host cell is a eukaryotic cell. 173. The host cell of embodiment 172, wherein the eukaryotic cell is a mammalian cell. 174. The host cell of embodiment 173, wherein the mammalian cell is a CHO cell or HEK cell. 175. A method of making the antibody of any one of embodiments 1-141, the method comprising expressing the nucleic acid of any one of embodiments 142-155 in the host cell of any one of embodiments 170-174. 176. A method of making the antibody of any one of embodiments 1-141, the method comprising performing an in vitro transcription reaction using the nucleic acid of any one of embodiments 142-155. 177. A method of reducing proliferation and/or activity of a population of T cells in a subject, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 178. A method of reducing proliferation and/or activity of a population of CD4+ T cells in a subject, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 179. A method of reducing proliferation and/or activity of a population of CD8+ T cells in a subject, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 180. The method of any one of embodiments 177-179, wherein the subject has been diagnosed as having an autoimmune disease. 181. The method of any one of embodiments 177-180, wherein the T cells are autoreactive T cells. 182. A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 183. The method of embodiment 180 or 182, wherein the autoimmune disease is an allograft rejection. 184. A method of treating graft-versus-host disease (GVHD) in a subject in need thereof, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 185. The method of embodiment 184, wherein the GVHD arises from a bone marrow transplant or one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T cells, B cells, natural killer cells, and dendritic cells. 186. A method of treating an allograft rejection in a subject in need thereof, the method comprising administering to the subject the antibody of any one of embodiments 1-141, the nucleic acid of any one of embodiments 142-155, or the pharmaceutical composition of any one of embodiments 156-169. 187. The method of embodiment 186, wherein the allograft rejection is skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, or organ graft rejection. 188. The method of any one of embodiments 177-187, wherein the subject is a mammalian subject. 189. The method of embodiment 188, wherein the mammalian subject is a human subject. 190. A kit comprising the antibody of any one of embodiments 1-141. 191. A kit comprising the nucleic acid of any one of embodiments 142-155. 192. A kit comprising the pharmaceutical composition of any one of embodiments 156-169. 193. The kit of any one of embodiments 190-192, wherein the kit further comprises a package insert instructing a user of the kit to administer the antibody, nucleic acid, or pharmaceutical composition to a subject. 194. The kit of embodiment 193, wherein the subject has been diagnosed as having an autoimmune disease, optionally wherein the subject has been diagnosed as having the autoimmune disease of embodiment 183. 195. The kit of embodiment 193, wherein the subject has been diagnosed as having GVHD, optionally wherein the subject has been diagnosed as having the GVHD of embodiment 185. 196. The kit of embodiment 193, wherein the subject has been diagnosed as having an allograft rejection. All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations described herein following, in general, the principles described herein and including such departures from the disclosure that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

CLAIMS 1. A binding protein, comprising a single-domain antibody that specifically binds CD28, the single-domain antibody comprising a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3).

2. The binding protein of claim 1, wherein the single-domain antibody comprises an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 41.

3. The binding protein of claim 1 or 2, wherein the single-domain antibody comprises an amino acid sequence of SEQ ID NO: 41.

4. The binding protein of any one of claims 1-3, further comprising a human serum albumin (HSA) protein attached to the single-domain antibody.

5. The binding protein of claim 4, wherein the HSA protein comprises an amino acid sequence of SEQ ID NO: 71 or SEQ ID NO: 157.

6. The binding protein of claim 4 or 5, wherein the HSA protein is attached to the single-domain antibody via a peptide linker.

7. The binding protein of claim 6, wherein the peptide linker comprises an amino acid sequence selected from any one of SEQ ID NOs: 72, 73, and 74.

8. The binding protein of any one of claims 1-7, wherein the binding protein comprises an amino acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the amino acid sequence of SEQ ID NO: 81.

9. The binding protein of any one of claims 1-8, wherein the binding protein comprises an amino acid sequence of SEQ ID NO: 81.

10. The binding protein of any one of claims 1-9, wherein the binding protein comprises a leader sequence of SEQ ID NO: 75.

11. A nucleic acid encoding the binding protein of any one of claims 1-10.

12. The nucleic acid of claim 11, wherein the nucleic acid is an mRNA.

13. The nucleic acid of claim 12, wherein the mRNA comprises, in the 5’-to-3’ direction: (a) a 5’ cap structure; (a) a 5’ untranslated region (UTR); (c) an open reading frame (ORF) encoding the antibody; (d) a 3’ UTR; and (e) a 3’ tailing sequence of linked nucleosides.

14. The nucleic acid of claim 13, wherein the ORF consists of nucleosides selected from the group consisting of (i) uridine or a modified uridine, (ii) cytidine or a modified cytidine, (iii) adenosine or a modified adenosine, and (iv) guanosine or a modified guanosine.

15. The nucleic acid of claim 13 or 14, wherein the 5’ UTR comprises a nucleic acid sequence of SEQ ID NO: 78.

16. The nucleic acid of any one of claims 13-15, wherein the 3’ UTR comprises a nucleic acid sequence of SEQ ID NO: 79.

17. The nucleic acid of any one of claims 13-16, wherein the ORF comprises a nucleic acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the nucleic acid sequence of SEQ ID NO: 77.

18. The nucleic acid of any one of claims 13-17, wherein the ORF comprises a nucleic acid sequence of SEQ ID NO: 77.

19. The nucleic acid of any one of claims 13-17, further comprising a poly(A) tail.

20. The nucleic acid of claim 19, wherein the poly(A) tail comprises or consists of 100 adenine residues.

21. An mRNA encoding the binding protein of any of claims 1-10, wherein the mRNA comprises, in the 5’-to-3’ direction: (a) a 5’ untranslated region (UTR) comprising a nucleic acid sequence of SEQ ID NO: 78; (b) an open reading frame (ORF) comprising the nucleic acid sequence of SEQ ID NO: 77; and (c) a 3’ UTR comprising a nucleic acid sequence of SEQ ID NO: 79.

22. A composition comprising the mRNA of claim 21 in the liquid nanoparticle LNP-1B.

23. A pharmaceutical composition, comprising the nucleic acid of any one of claims 11-21.

24. The pharmaceutical composition of claim 23, further comprising a lipid nanoparticle.

25. The pharmaceutical composition of claim 24, wherein the lipid nanoparticle comprises: (a) an ionizable lipid of Formula (I):

wherein

, wherein

denotes a point of attachment; wherein R¹⁰ is N(R)₂; each R is independently selected from the group consisting of C_1-6 alkyl, C_2-3 alkenyl, and H; wherein n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each R⁵ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; each R⁶ is independently selected from the group consisting of C_1-3 alkyl, C_2-3 alkenyl, and H; M and M’ are each independently selected from the group consisting of -C(O)O- and -OC(O)-; R’ is a C_1-12 alkyl or C_2-12 alkenyl; l is selected from the group consisting of 1, 2, 3, 4, and 5; and m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13.

26. The pharmaceutical composition of claim 25, wherein the ionizable lipid of Formula (I) comprises: R’^a is R’^branched; R’^branched is

denotes a point of attachment; and R^aα is C_2-12 alkyl; R^aβ, R^aγ, and R^aδ are each H; R² and R³ are each C_1-14 alkyl; R⁴ is

; R¹⁰ is NH(C_1-6 alkyl); n2 is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7.

27. The pharmaceutical composition of claim 25, wherein the ionizable lipid of Formula (I) comprises: R’a is R’branched; R’branched is

;

denotes a point of attachment; R^aα, R^aβ, R^aγ, and R^aδ are each H; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R5 is H; each R6 is H; M and M’ are each -C(O)O-; R’ is a C1-12 alkyl; l is 5; and m is 7.

28. The pharmaceutical composition of claim 25, wherein the ionizable lipid of Formula (I) comprises: R’a is R’branched; R’branched is

;

denotes a point of attachment; R^aβ and R^aδ are each H; R^aγ is C_2-12 alkyl; R² and R³ are each C_1-14 alkyl; R⁴ is -(CH₂)_nOH; n is 2; each R⁵ is H; each R⁶ is H; M and M’ are each -C(O)O-; R’ is a C_1-12 alkyl; l is 5; and m is 7.

29. The pharmaceutical composition of claim 24, wherein the lipid nanoparticle comprises an ionizable lipid selected from: , and

or N-oxides, salts, or isomers thereof.

30. The pharmaceutical composition of any one of claims 24-29, wherein the lipid nanoparticle further comprises: a phospholipid, a structural lipid, and a PEG-lipid.

31. The pharmaceutical composition of any one of claims 24-30, wherein the lipid nanoparticle comprises: 40-50 mol% of an ionizable lipid, 30-45 mol% of a structural lipid, 5-15 mol% of a phospholipid, and 1-5 mol% of a PEG-lipid.

32. The pharmaceutical composition of claim 31, wherein the lipid nanoparticle comprises: 45-50 mol% of the ionizable lipid, 35-40 mol% of the structural lipid, 8-12 mol% of the phospholipid, and 1.5-3.5 mol% of the PEG-lipid.

33. The pharmaceutical composition of any one of claims 30-32, wherein the phospholipid is selected from: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-gly cero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2 cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine,1,2-diarachidonoyl-sn-glycero-3- phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero- 3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof.

34. The pharmaceutical composition of any one of claims 30-33, where the phospholipid is DSPC.

35. The pharmaceutical composition of any one of claims 30-34, wherein the structural lipid is selected from: cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha-tocopherol, hopanoids, phytosterols, steroids, derivatives thereof, and mixtures thereof.

36. The pharmaceutical composition of any one of claims 30-35, wherein the structural lipid is cholesterol or a derivative thereof.

37. The pharmaceutical composition of any one of claims 30-36, wherein the PEG-lipid is selected from: 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl- sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), PEG-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA), any mixtures thereof.

38. The pharmaceutical composition of any one of claims 30-37, wherein the PEG-lipid comprises a structure of:

.

39. The pharmaceutical composition of any one of claims 24-38, wherein the lipid nanoparticle comprises: 40-50 mol% of an ionizable lipid comprising a structure of:

, 30-45 mol% of cholesterol, 5-15 mol% of DSPC, and 1-5 mol% of a PEG-lipid.

40. A single-domain antibody that specifically binds CD28 and comprises the following complementarity-determining regions (CDRs): (a) a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3); (b) a CDR-1 having the amino acid sequence GDTICGNV (SEQ ID NO: 4), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3); (c) a CDR-1 having the amino acid sequence GSIFSINA (SEQ ID NO: 5), a CDR-2 having the amino acid sequence ITSGGST (SEQ ID NO: 6), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3); (d) a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AAGPPWWRYGGGSSWYERPREYDY (SEQ ID NO: 7); (e) a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADRTGQTVQATYWEYDY (SEQ ID NO: 8); (f) a CDR-1 having the amino acid sequence GFTLDYYA (SEQ ID NO: 9), a CDR-2 having the amino acid sequence ISSSHGST (SEQ ID NO: 10), and a CDR-3 having the amino acid sequence VVFWGPSVDMITGA (SEQ ID NO: 11); (g) a CDR-1 having the amino acid sequence GFTLDYYA (SEQ ID NO: 9), a CDR-2 having the amino acid sequence ITSGGST (SEQ ID NO: 6), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3); (h) a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence AADLWGSSWYSAVPGNDY (SEQ ID NO: 12); (i) a CDR-1 having the amino acid sequence GDTICISA (SEQ ID NO: 13), a CDR-2 having the amino acid sequence ITSGGST (SEQ ID NO: 6), and a CDR-3 having the amino acid sequence AADNWGIVRWRAPDY (SEQ ID NO: 3); (j) a CDR-1 having the amino acid sequence GSVFSGNV (SEQ ID NO: 1), a CDR-2 having the amino acid sequence ITSGGSA (SEQ ID NO: 2), and a CDR-3 having the amino acid sequence HPLSLASSWYSS (SEQ ID NO: 14); (k) a CDR-1 having the amino acid sequence GRTYSTYN (SEQ ID NO: 15), a CDR-2 having the amino acid sequence ISWTGSNT (SEQ ID NO: 16), and a CDR-3 having the amino acid sequence ATELEFYNRRWPPTLDY (SEQ ID NO: 17); (l) a CDR-1 having the amino acid sequence GRTFGNYV (SEQ ID NO: 18), a CDR-2 having the amino acid sequence IRWSDGTT (SEQ ID NO: 19), and a CDR-3 having the amino acid sequence AADVHGELFPQVQSHYDY (SEQ ID NO: 20); or (m) a CDR-1 having the amino acid sequence GRTFSAYC (SEQ ID NO: 21), a CDR-2 having the amino acid sequence IMWSDGST (SEQ ID NO: 22), and a CDR-3 having the amino acid sequence AAGVCDSSRLLTRKYEYGY (SEQ ID NO: 23).

41. An antibody, or antigen-binding fragment thereof, that specifically binds CD28 and comprises the following CDRs: (i) (a) a CDR-L1 having the amino acid sequence ESVYSDNR (SEQ ID NO: 24), (b) a CDR-L2 having the amino acid sequence LAS (SEQ ID NO: 25), (c) a CDR-L3 having the amino acid sequence AGFKIRGTDGHG (SEQ ID NO: 26), (d) a CDR-H1 having the amino acid sequence GFSFHFTYW (SEQ ID NO: 27), (e) a CDR-H2 having the amino acid sequence IHAGSTGTT (SEQ ID NO: 28), and (f) a CDR-H3 having the amino acid sequence ARLDDIDDYFNL (SEQ ID NO: 29); (ii) (a) a CDR-L1 having the amino acid sequence QSIYSD (SEQ ID NO: 30), (b) a CDR-L2 having the amino acid sequence AAA (SEQ ID NO: 31), (c) a CDR-L3 having the amino acid sequence QSFHGYSGTYG (SEQ ID NO: 32), (d) a CDR-H1 having the amino acid sequence GLSFNVYW (SEQ ID NO: 33), (e) a CDR-H2 having the amino acid sequence IGPSGDGKT (SEQ ID NO: 34), and (f) a CDR-H3 having the amino acid sequence ARDYTNAFDL (SEQ ID NO: 35); or (iii) (a) a CDR-L1 having the amino acid sequence QNIYSD (SEQ ID NO: 36), (b) a CDR-L2 having the amino acid sequence AAA (SEQ ID NO: 31), (c) a CDR-L3 having the amino acid sequence QGFHGSSGSHG (SEQ ID NO: 37), (d) a CDR-H1 having the amino acid sequence GFSDRYW (SEQ ID NO: 38), (e) a CDR-H2 having the amino acid sequence ISAGSNAKT (SEQ ID NO: 39), and (f) a CDR-H3 having the amino acid sequence ARDYANYFDL (SEQ ID NO: 40).

42. The antibody of claim 40 or 41, wherein the antibody comprises a heavy chain variable domain having an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 42-63, 65, 67, and 69.

43. The antibody of any one of claims 40-42, wherein the antibody comprises a light chain variable domain having an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 64, 66, and 68.

44. The antibody of any one of claims 40-43, wherein: (i) the antibody inhibits CD28 signaling; (ii) the antibody binds CD28 with a K_D of no greater than 100 nM; (iii) the antibody binds CD28 with a K_D of from 1 nM to 100 nM; (iv) the antibody binds CD28 with a k_on of from 10³ M^-1s^-1 to 10⁵ M^-1s^-1; (v) wherein the antibody binds CD28 with a k_off of from 10^-4 s^-1 to about 10^-5 s^-1; (vi) the antibody reduces expression of one or more proteins selected from CTLA-4, CD80, CD86, CD95, YMNM, PI3K, PIP3, AKT, IL2, mTOR, and BCL-XL in a CD28- expressing T cell; (vii) the antibody inhibits GrB and/or PD-1 activation in a CD28-expressing T cell; (viii) the antibody reduces proliferation and/or activity of CD4+ T cells in a subject, optionally wherein the CD4+ T cells are autoreactive T cells; (ix) the antibody reduces proliferation and/or activity of CD8+ T cells in a subject, optionally wherein the CD8+ T cells are autoreactive T cells; or (x) any combination thereof.

45. The antibody of any one of claims 41-44, wherein the antibody is a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual- variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a domain antibody, a Fv fragment, a Fab fragment, a F(ab’)₂ molecule, or a tandem scFv (taFv).

46. A nucleic acid encoding the antibody of any one of claims 40-45.

47. The nucleic acid of claim 46, wherein the nucleic acid is an mRNA.

48. The nucleic acid of claim 46 or 47, wherein the nucleic acid comprises, in the 5’-to-3’ direction: (a) a 5’ cap structure; (a) a 5’ untranslated region (UTR); (c) an open reading frame encoding the antibody, wherein the open reading frame consists of nucleosides selected from the group consisting of (i) uridine or a modified uridine, (ii) cytidine or a modified cytidine, (iii) adenosine or a modified adenosine, and (iv) guanosine or a modified guanosine; (d) a 3’ UTR; and (e) a 3’ tailing sequence of linked nucleosides.

49. The nucleic acid of claim 48, wherein the open reading frame of nucleosides selected from the group consisting of (i) a modified uridine, (ii) cytidine, (iii) adenosine, and (iv) guanosine.

50. The nucleic acid of claim 48 or 49, wherein the modified uridine is 1- methylpseudouridine, pseudouridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza- uridine, 2-thio-5-aza-uridine, 2-thio-uridine, 4-thio-uridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxy-uridine, 5-aminoallyl-uridine, 5-halo-uridine, 3-methyl-uridine, 5-methoxy-uridine, uridine 5-oxyacetic acid, uridine 5-oxyacetic acid methyl ester, 5- carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl- uridine, 5-carboxyhydroxymethyl-uridine methyl ester, 5-methoxycarbonylmethyl- uridine, 5-methoxycarbonylmethyl-2-thio-uridine, 5-aminomethyl-2-thio-uridine, 5- methylaminomethyl-uridine, 5-methylaminomethyl-2-thio-uridine, 5-methylaminomethyl- 2-seleno-uridine, 5-carbamoylmethyl-uridine, 5-carboxymethylaminomethyl-uridine, 5- carboxymethylaminomethyl-2-thio-uridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine, 5-methyl-2-thio-uridine, 1- methyl-4-thio-pseudouridine, 4-thio-1-methyl-pseudouridine, 3-methylpseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza- pseudouridine, dihydrouridine, dihydropseudouridine, 5,6-dihydrouridine, 5-methyl- dihydrouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2- methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1- methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine, 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine, 5-(isopentenylaminomethyl)uridine, 5- (isopentenylaminomethyl)-2-thio-uridine, α-thio-uridine, 2′-O-methyl-uridine, 5,2′-O- dimethyl-uridine, 2′-O-methyl-pseudouridine, 2-thio-2′-O-methyl-uridine, 5- methoxycarbonylmethyl-2′-O-methyl-uridine, 5-carbamoylmethyl-2′-O-methyl-uridine, 5- carboxymethylaminomethyl-2′-O-methyl-uridine, 3,2′-O-dimethyl-uridine, 5- (isopentenylaminomethyl)-2′-O-methyl-uridine, 1-thio-uridine, deoxythymidine, 2’-F-ara- uridine, 2’-F-uridine, 2’-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, or 5-[3-(1-E- propenylamino)uridine.

51. The nucleic acid of claim 48, wherein the modified uridine is 1- methylpseudouridine.

52. The nucleic acid of any one of claims 48, 50, and 51, wherein the modified cytidine is 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4- acetyl-cytidine, 5-formyl-cytidine, N4-methyl-cytidine, 5-methyl-cytidine, 5-halo-cytidine, 5-hydroxymethyl-cytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo- pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4- thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl- 1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2- thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4- methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, lysidine, α-thio- cytidine, 2′-O-methyl-cytidine, 5,2′-O-dimethyl-cytidine, N4-acetyl-2′-O-methyl-cytidine, N4,2′-O-dimethyl-cytidine, 5-formyl-2′-O-methyl-cytidine, N4,N4,2′-O-trimethyl-cytidine, 1-thio-cytidine, 2’-F-ara-cytidine, 2’-F-cytidine, or 2’-OH-ara-cytidine.

53. The nucleic acid of any one of claims 48 and 50-52, wherein the modified adenosine is 2-amino-purine, 2, 6-diaminopurine, 2-amino-6-halo-purine, 6-halo-purine, 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2,6-diaminopurine, 7- deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine, 2-methyl-adenine, N6-methyl- adenosine, 2-methylthio-N6-methyl-adenosine, N6-isopentenyl-adenosine, 2-methylthio- N6-isopentenyl-adenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6- (cis-hydroxyisopentenyl)adenosine, N6-glycinylcarbamoyl-adenosine, N6- threonylcarbamoyl-adenosine, N6-methyl-N6-threonylcarbamoyl-adenosine, 2- methylthio-N6-threonylcarbamoyl-adenosine, N6,N6-dimethyl-adenosine, N6- hydroxynorvalylcarbamoyl-adenosine, 2-methylthio-N6-hydroxynorvalylcarbamoyl- adenosine, N6-acetyl-adenosine, 7-methyl-adenine, 2-methylthio-adenine, 2-methoxy- adenine, α-thio-adenosine, 2′-O-methyl-adenosine, N6,2′-O-dimethyl-adenosine, N6,N6,2′-O-trimethyl-adenosine, 1,2′-O-dimethyl-adenosine, 2′-O-ribosyladenosine, 2- amino-N6-methyl-purine, 1-thio-adenosine, 8-azido-adenosine, 2’-F-ara-adenosine, 2’- F-adenosine, 2’-OH-ara-adenosine, or N6-(19-amino-pentaoxanonadecyl)-adenosine.

54. The nucleic acid of any one of claims 48 and 50-53, wherein the modified guanosine is inosine, 1-methyl-inosine, wyosine, methylwyosine, 4-demethyl-wyosine, isowyosine, wybutosine, peroxywybutosine, hydroxywybutosine, 7-deaza-guanosine, queuosine, epoxyqueuosine, galactosyl-queuosine, mannosyl-queuosine, 7-cyano-7- deaza-guanosine, 7-aminomethyl-7-deaza-guanosine, archaeosine, 7-deaza-8-aza- guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza- guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6- methoxy-guanosine, 1-methyl-guanosine, N2-methyl-guanosine, N2,N2-dimethyl- guanosine, N2,7-dimethyl-guanosine, N2, N2,7-dimethyl-guanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, α-thio-guanosine, 2′-O-methyl-guanosine, N2-methyl- 2′-O-methyl-guanosine, N2,N2-dimethyl-2′-O-methyl-guanosine, 1-methyl-2′-O-methyl- guanosine, N2,7-dimethyl-2′-O-methyl-guanosine, 2′-O-methyl-inosine, 1,2′-O-dimethyl- inosine, 2′-O-ribosylguanosine, 1-thio-guanosine, O6-methyl-guanosine, 2’-F-ara- guanosine, or 2’-F-guanosine.

55. The nucleic acid of any one of claims 48-54, wherein the 3’ tailing sequence of linked nucleosides is a poly-adenylate (polyA) tail or a polyA-G quartet.

56. The nucleic acid of claim 55, wherein the 3’ tailing sequence of linked nucleosides is a polyA tail.

57. The nucleic acid of any one of claims 48-56, wherein the 5’ cap structure is Cap0, Cap1, ARCA, inosine, 1-methyl-guanosine, 2′fluoroguanosine, 7-deaza- guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, or 2- azidoguanosine.

58. A pharmaceutical composition comprising the antibody of any of claims 40-45 or the nucleic acid of any one of claims 46-57.

59. The pharmaceutical composition of claim 58, further comprising one or more pharmaceutically acceptable carriers, diluents, and/or excipients.

60. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises a plurality of lipid nanoparticles encapsulating the nucleic acid.

61. The pharmaceutical composition of claim 60, wherein the plurality of lipid nanoparticles has a mean particle size of from 80 nm to 160 nm.

62. The pharmaceutical composition of claim 60 or 61, wherein the plurality of lipid nanoparticles has a polydispersity index (PDI) of from 0.02 to 0.2 and/or a lipid:nucleic acid ratio of from 10 to 20.

63. The pharmaceutical composition of any one of claims 60-62, wherein the lipid nanoparticles comprise a neutral lipid, an ionizable cationic lipid, a polyethyleneglycol (PEG) lipid, and/or a sterol.

64. The pharmaceutical composition of claim 63, wherein the neutral lipid is 1,2- distearoyl-sn-glycero-3-phosphocholine.

65. The pharmaceutical composition of claim 63 or 64, wherein the cationic lipid is selected from:

, or N-oxides, salts, or isomers thereof.

66. The pharmaceutical composition of any one of claims 63-65, wherein the PEG lipid is PEG 2000 dimyristoyl glycerol.

67. The pharmaceutical composition of any one of claims 63-66, wherein the sterol is cholesterol, adosterol, agosterol A, atheronals, avenasterol, azacosterol, blazein, cerevisterol, colestolone, cycloartenol, daucosterol, 7-dehydrocholesterol, 5- dehydroepisterol, 7-dehydrositosterol, 20α,22R-dihydroxycholesterol, dinosterol, epibrassicasterol, episterol, ergosterol, ergosterol, fecosterol, fucosterol, fungisterol, ganoderenic acid, ganoderic acid, ganoderiol, ganodermadiol, 7α-hydroxycholesterol, 22R-hydroxycholesterol, 27-hydroxycholesterol, inotodiol, lanosterol, lathosterol, lichesterol, lucidadiol, lumisterol, oxycholesterol, oxysterol, parkeol, saringosterol, spinasterol, sterol ester, trametenolic acid, zhankuic acid, or zymosterol.

68. The pharmaceutical composition of claim 67, wherein the sterol is cholesterol.

69. A host cell comprising the antibody of any of claims 40-45 or the nucleic acid of any one of claims 46-57.

70. The host cell of claim 69, wherein the host cell is a eukaryotic cell.

71. The host cell of claim 70, wherein the eukaryotic cell is a mammalian cell.

72. The host cell of claim 71, wherein the mammalian cell is a CHO cell or HEK cell.

73. A method of reducing proliferation and/or activity of a population of autoreactive T cells in a subject, the method comprising administering to the subject the binding protein of any one of claims 1-9, the antibody of any one of claims 40-45, the nucleic acid of any one of claims 10-20and 46-57, the composition of claim 21, or the pharmaceutical composition of any one of claims 22-39 and 58-68.

74. The method of claim 73, wherein the subject has been diagnosed as having an autoimmune disease.

75. A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject the binding protein of any one of claims 1-9, the antibody of any one of claims 40-45, the nucleic acid of any one of claims 10-20 and 46-57, the mRNA of claim 21, the composition of claim 22, or the pharmaceutical composition of any one of claims 23-39 and 58-68.

76. The method of claim 74 or 75, wherein the autoimmune disease is an allograft rejection.

77. A method of treating graft-versus-host disease (GVHD) in a subject in need thereof, the method comprising administering to the subject the binding protein of any one of claims 1-9, the antibody of any one of claims 40-45, the nucleic acid of any one of claims 10-20 and 46-57, the mRNA of claim 21, the composition of claim 22, or the pharmaceutical composition of any one of claims 23-39 and 58-68.

78. The method of claim 77, wherein the GVHD arises from a bone marrow transplant or one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T cells, B cells, natural killer cells, and dendritic cells.

79. A method of treating an allograft rejection in a subject in need thereof, the method comprising administering to the subject the binding protein of any one of claims 1-9, the antibody of any one of claims 40-45, the nucleic acid of any one of claims 10-20 and 46-57, the mRNA of claim 21, the composition of claim 22, or the pharmaceutical composition of any one of claims 23-39 and 58-68.

80. The method of claim 79, wherein the allograft rejection is skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, or organ graft rejection.

81. The method of any one of claims 73-80, wherein the subject is a human.

82. A kit comprising the binding protein of any one of claims 1-9, the antibody of any one of claims 40-45, the nucleic acid of any one of claims 10-20 and 46-57, the mRNA of claim 21, the composition of claim 22, or the pharmaceutical composition of any one of claims 23-39 and 58-68, wherein the kit further comprises a package insert instructing a user of the kit to administer the antibody, nucleic acid, or pharmaceutical composition to a subject in need thereof.