WO2024084056A1 - Ionizable lipids - Google Patents

Ionizable lipids Download PDF

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Publication number
WO2024084056A1
WO2024084056A1 PCT/EP2023/079320 EP2023079320W WO2024084056A1 WO 2024084056 A1 WO2024084056 A1 WO 2024084056A1 EP 2023079320 W EP2023079320 W EP 2023079320W WO 2024084056 A1 WO2024084056 A1 WO 2024084056A1
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instance
6alkyl
optionally
independently
independently selected
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PCT/EP2023/079320
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French (fr)
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Sabah KASMI
Ruben DE COEN
Stefaan De Koker
Shrinivas DUMBRE
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Etherna Immunotherapies Nv
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Publication of WO2024084056A1 publication Critical patent/WO2024084056A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

Definitions

  • the present invention generally relates to the field of lipids, in particular ionizable (also termed cationic) lipids, and in particular provides a novel type of such lipids as represented by any of the formulae disclosed herein.
  • the present invention further provides methods for making such lipids as well as uses thereof, in particular in the preparation of nanoparticle compositions, more in particular nanoparticle compositions comprising nucleic acids. It further provides pharmaceutical formulations comprising nanoparticle compositions based on the ionizable lipids disclosed herein.
  • Nanoparticles such as liposomes and lipid nanoparticles are increasingly being used in therapeutic areas for the delivery of active agents, such as small molecules, proteins, nucleic acids, etc. to cells.
  • active agents such as small molecules, proteins, nucleic acids, etc.
  • One of the main requirements for medical use of nanoparticles is that they need to combine efficient and stable encapsulation of the active agents upon storage and in the extracellular environment, with maximum cellular uptake and efficient release of their payload into the cells.
  • lipid-based nanoparticles comprising combinations of cationic lipids with other lipid components have been used to facilitate such cellular uptake of active agents.
  • lipid-based nanoparticles are typically composed of a cationic or ionizable lipid that can be protonated at acid pH, a helper lipid (e.g. phospholipid), a stabilizing lipid (e.g. PEGylated lipid) and a sterol, and have been used in the delivery of nucleic acids.
  • Each component of a nanoparticle has specialized functions in stability and activity of the nanoparticles. Therefore, further improvements in cationic or ionizable lipid chemistries are needed to improve efficacy and safety of nanoparticle delivered active agents.
  • the present invention relates to a new class of ionizable lipids as defined by the present set of claims, which have improved characteristics over the currently available classes of ionizable lipids.
  • the present invention provides a lipid, in particular an ionizable lipid represented by formula (I) n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C
  • the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I) (I) n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R 2 is independently selected from -C 1-20 alkyl, -C 2-20 alkenyl and -C 2-20 alky
  • the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I) 0 n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R 2 is independently selected from -C 1-20 alkyl, -C 2-20 alkenyl and -C 2-20 alkyn
  • the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I) wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkyn
  • the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I) wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkyn
  • the present invention provides a lipid, in particular an ionizable lipid being represented by formula (Ia) m is an integer selected from 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl
  • each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 5 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X4, X5, R6 and R6’, the total number of C atoms of in X4, X5, R6 and R6’ together with the N atom to which
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIb) wherein n is 1: m is 3; each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, -C8- 20alkenyl and -C8-20alkynyl; wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined herein.
  • formula (IIIb) wherein n is 1: m is 3; each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, -C8- 20alkenyl and -C8-20alkyny
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Va), formula (VaN), formula (Va’), formula (Va’N), formula (Vb), formula (VbN), formula (Vb’), formula (Vb’N), formula (Vc), formula (VcN), formula (Vd), formula (VdN), formula (Vd’), formula (Vd’N), formula (Ve) or formula (VeN)
  • the present invention provides an ionizable lipid represented by formula (VII)
  • the present invention provides an ionizable lipid represented by formula (VIIIa), or formula (VIIIb) wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein the total number of C atoms in X1, X2, X3, R5 and R5’ together is at least 5; and wherein Y1, Y2, Z, B1, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention.
  • the present invention provides an ionizable lipid represented by formula (IXa), or formula (IXb)
  • each instance of X 4 and each instance of X 5 is independently selected from -C 1-20 alkylene-, -C 2- 20alkenylene-, and -C2-20alkynylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein the total number of C atoms in X4, X5, R6 and R6’ together is at least 6; wherein Y1, Y2, Z, B1, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention.
  • the present invention provides an ionizable lipid represented by formula (Xa), formula (Xb), formula (Xc), formula (Xd), or formula (Xe)
  • Y1, Y2, Z, B1, R1, R2, R3, R4, R4, and m are as defined any one of the embodiments of the present invention.
  • the present invention provides an ionizable lipid wherein n is 1.
  • the present invention provides an ionizable lipid wherein m is an integer selected from 1, 2, and 3.
  • the present invention provides an ionizable lipid wherein each instance of R1 and each instance of R2 is independently selected from -H, and -C1-8alkyl; wherein each of said -C1- 8alkyl is independently substituted with from 1 to 3 substituents independently selected from - OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; and wherein the total number of C atoms in R1 and R2 together is at least 8.
  • the present invention provides an ionizable lipid wherein each instance of Y1 is independently selected from a direct bond, and -CH2-.
  • the present invention provides an ionizable lipid wherein each instance of Y2 is independently selected from -O-.
  • the present invention provides an ionizable lipid wherein each instance of Z is independently selected from -C1-3alkylene-.
  • the present invention provides an ionizable lipid wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being selected from the list comprising:
  • the present invention provides a lipid nanoparticle or lipid nanoparticle composition
  • a lipid in particular an ionizable lipid as defined herein.
  • Said nanoparticle composition may further comprise additional lipids either or not acting as stabilizers, such as a phospholipid, a sterol and/or a PEG lipid.
  • the lipid nanoparticle or lipid nanoparticle composition as defined herein further comprises an active agent, in particular a nucleic acid, preferably mRNA.
  • the present invention provides the use of a lipid, in particular an ionizable lipid as defined herein in the manufacture of a lipid nanoparticle or lipid nanoparticle composition.
  • the present invention provides a lipid, in particular an ionizable lipid represented by formula (I) wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nanoparticles as defined herein and a pharmaceutically acceptable agent, such as a carrier, excipient, etc.
  • a pharmaceutically acceptable agent such as a carrier, excipient, etc.
  • Such pharmaceutical compositions are particularly suitable in various fields such as prophylactic vaccines, therapeutic vaccines, protein replacement therapies, gene editing, gene silencing, small molecule delivery, etc.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 (FIG.1) shows a representation of the viability of HEK 293T cells after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations.
  • FIG.2 shows a representation of the relative Mean Fluorescence Intensity (MFI) in HEK 293T cells of eGFP after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations.
  • Figure 3 shows a representation of the viability of HEK 293T cells after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations.
  • Figure 4 shows a representation of the relative Mean Fluorescence Intensity (MFI) in HEK 293T cells of eGFP after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations.
  • FIG. 5 shows a representation of the Average Radiance measured in vivo (supine view) for different LNP formulations containing Fluc mRNA.
  • Figure 6 shows a representation of the Average Radiance measured ex vivo for different LNP formulations containing Fluc mRNA.
  • Figure 7 shows a representation of the average hEPO levels measured in blood at different timepoints 24 h post injection. The three injections were administered with a weekly interval. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary.
  • any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
  • asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.
  • the present invention provides a lipid, in particular an ionizable lipid represented by formula (I) wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C
  • alkyl by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula C x H 2x+1 wherein x is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 20 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • C1-4alkyl means an alkyl of one to four carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. n-butyl, i-butyl and t- butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, tridecyl and its isomers, tetradecyl and its isomers, pentadecyl and its isomers, hexadecyl and its isomers, heptadecyl and its isomers, octadecyl and its isomers, nonadecyl and its isomers, eicosanyl and its isomers.
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3, or 4 substituents) at any available point of attachment.
  • substituents include esters, carboxylic acids, alkyl moieties, alkene moieties, alkyne moieties, ... and the like.
  • an alkyl group for example -C 1-6 alkyl, being optionally substituted, it also refers to groups comprising said alkyl group, for example -O-C1-6alkyl, -OC(O) -C1-6alkyl, -C(O)O-C1-6alkyl, and the like.
  • the alkyl, alkenyl and alkynyl moieties as defined herein may also further comprise one or more heteroatoms, such as selected from N, S or O, in that for example a carbon atom in an alkyl, alkene or alkyne chain is replaced by a heteroatom.
  • the heteroatoms may be adjacent or separated, as long as it results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • An example of a stable combination of two adjacent heteroatoms is a disulfide (-S-S-) group.
  • alkenyl or “alkene”, as used herein, unless otherwise indicated, means straight-chain, cyclic, or branched-chain hydrocarbon radicals containing at least one carbon-carbon double bond.
  • alkenyl radicals include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, be it in the terminal or internal positions and the like.
  • alkenyl or alkene moieties of the present invention comprise from 2 to 20 C atoms.
  • An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
  • alkynyl as used herein, unless otherwise indicated, means straight-chain or branched-chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl, hexynyl, hexadiynyl, be it in the terminal or internal positions, and the like.
  • An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
  • the term “cycloalkyl” by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1, 2, or 3 cyclic structure.
  • Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 15 atoms.
  • cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl and cyclodecyl with cyclopropyl being particularly preferred.
  • An “optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, for example 1, 2, 3 or 4 substituents), selected from those defined above for substituted alkyl.
  • alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed “alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene and hexamethylene.
  • alkenyl groups as defined above and alkynyl groups as defined above, respectively are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene” and "alkynylene” respectively.
  • heterocycle refers to non- aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
  • substituents for example 1 to 4 substituents, or for example 1, 2, 3 or 4
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, ....
  • the aryl ring or heterocycle as defined herein can optionally be substituted by one or more substituents (for example 1 to 5 substituents, for example 1, 2, 3 or 4) at any available point of attachment.
  • substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO2-NH2, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkyl, al
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • heteroaryl include: piridinyl, azepinyl,...
  • An “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3 or 4), selected from those defined above for substituted aryl.
  • substituents for example 1 to 4 substituents, for example 1, 2, 3 or 4
  • alkoxy or “alkyloxy” as used herein refers to a radical having the Formula -OR x wherein R x is alkyl.
  • alkoxy is C1-C10 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy.
  • suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the oxygen atom in an alkoxy group is substituted with sulfur, the resultant radical is referred to as thioalkoxy.
  • “Haloalkoxy” is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen.
  • Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
  • the term "carboxy” or “carboxyl” or “hydroxycarbonyl” by itself or as part of another substituent refers to the group -CO2H.
  • a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -CO2H.
  • alkoxycarbonyl by itself or as part of another substituent refers to a carboxy group linked to an alkyl radical i.e. to form -C(O)ORe, wherein Re is as defined above for alkyl.
  • alkylcarbonyloxy by itself or as part of another substituent refers to a -O-C(O)Re wherein Re is as defined above for alkyl.
  • substituted is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice.
  • Substituents may be selected from, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano, haloalkoxy, and haloalkyl.
  • alkyl, aryl, or cycloalkyl, each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • lipid is meant to be a chemically defined substance that is insoluble in water but soluble in amongst others alcohol, ether and chloroform.
  • Ionizable or cationic lipids are lipids that are typically composed of three sections: an amine head group, a linker moiety and a hydrophobic tail.
  • the term “ionizable” (or alternatively cationic) in the context of a compound or lipid means the presence of any uncharged group in said compound or lipid which is capable of dissociating by yielding an ion (usually an H + ion) and thus itself becoming positively charged. Alternatively, any uncharged group in said compound or lipid may yield an electron and thus becoming negatively charged.
  • lipids as defined herein may occur as different isomers/stereomers.
  • the lipids as defined herein may occur in the trans or cis configuration, such as when they contain double bonds.
  • the lipids as defined herein occur in the cis configuration.
  • the term ‘cis’ indicates that the functional groups are on the same side of a plane, whereas ‘trans’ means that they are on opposite sides.
  • each stereocenter may have the R or S configuration, unless stated otherwise.
  • the compound may therefore be a racemic mixture of enantiomers and/or diastereoisomers, or it may have an excess of one or more of the enantiomers and/or diastereoisomers, such as more than 60 %, more than 70 %, more than 80 %, more than 85 %, more than 90 %, more than 95 %, more than 98 %, more than 99 %.
  • Vitamin B derivatives e.g. pyridoxine, pyridoxamine, pyridoxal
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I) wherein one or more of the following applies: n is an integer selected from 1, 2, and 3; In particular n is an integer selected from 1, and 2; More in particular n is 1; m is an integer selected from 0, 1, 2, 3, and 4; In particular m is an integer selected from 1, 2, 3, and 4; More in particular m is an integer selected from 1, 2, and 3; Even more in particular m is 3; wherein the sum of n and m is at least 4; In particular wherein the sum of n and m is 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from
  • each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom;
  • each instance of Cy1 is independently a 5- to 7-membered non-aromatic cycle comprising at least 1 N atom, optionally and independently comprising 1 to 4 additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; More in particular each instance of
  • each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; and More in particular each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and -Bn;
  • an ionizable lipid is provided by the present invention, wherein the sum of n and m is at least 4, such as 4 or 5. In specific embodiments of the invention, the sum of n and m is 4. In specific embodiments of the invention, n is an integer selected from 1, and 2. In preferred embodiments of the invention, n is 1.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia); wherein m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said
  • m is an integer selected from 1, 2, 3, and 4. In other specific embodiments of the invention, m is an integer selected from 2, 3, and 4. In preferred embodiments of the invention, m is 3.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7.
  • an ionizable lipid is provided by the present invention, wherein each instance of R2 5 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7.
  • an ionizable lipid is provided by the present invention, wherein each instance of R 1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; and each instance of R 2 is independently selected from -C 1-20 alkyl; wherein each of said -C 1-20 alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7.
  • an ionizable lipid is provided by the present invention, wherein each instance of R7 is independently selected from -C1-20alkyl, and -C2-20alkenyl; wherein each of said -C1-20alkyl, and -C2-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R 7 , and -C(O)O-R 7 ; and each instance of R7 is independently selected from -C1-20alkyl, and -C2-20alkenyl; wherein each of said -C
  • an ionizable lipid is provided by the present invention, wherein each instance of R7 is independently selected from -C8-20a y, a d C8-20alkenyl; wherein each of said -C8-20alkyl, and -C8-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents;
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more hetero
  • an ionizable lipid is provided by the present invention, wherein each instance of R 1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8- 2 0 alkenyl; and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20al
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R 2 is independently selected from -C 1-20 alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein an ionizable lipid is provided as defined herein, wherein each instance of R 1 and each instance of R 2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2- 2 0 alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R 1 is -H; and each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7.
  • an ionizable lipid is provided by the present invention, wherein each instance of Y is independently selected from a direct bond, and -CH2-.
  • an ionizable lipid is provided by the present invention, wherein each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, -NRaC(O)O-, and - OC(O)NRa-.
  • an ionizable lipid is provided by the present invention, wherein each instance of FG is independently selected from -OC(O)-, and -NRaC(O)-.
  • an ionizable lipid is provided as defined herein, wherein each instance of FG is independently selected from -OC(O)-, and -NHC(O)- .
  • an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 1 2 alkenylene-, and -C 2-12 alkynylene; wherein each of said -C 1-12 alkylene-, -C 2-12 alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from a direct bond, and C1-12alkylene-.
  • an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from -C1-12alkylene-.
  • an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H.
  • an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH 3 , -OH, -CH 2 -OH, -CH 2 -SH, -CH 2 -NR 4 R 4’ , and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia); wherein m is an integer selected from 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkeny
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia); wherein m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O- C8-20alkyl, and -C(O)O-C8-20alkenyl.
  • formula (Ia) ionizable lipid as defined herein and being represented by formula (Ia); wherein m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C
  • each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of Y is independently selected from a direct bond, and -CH2-; 5 each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6al
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-20alkyl; wherein each of said -C1-20alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -OC(O)- C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and -C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R 2 is -C 1-20 alkyl; wherein each of said -C 1-20 alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)- C8-20alkynyl, -C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-20alkyl; wherein each of said -C1-20alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)- C8-20alkynyl, -C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with 2 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R 1 and R 2 , the total number of C atoms of R 1 and R 2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, - C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and -C(O)O-C2-20alkynyl; wherein in each instance of R 1 and R 2 , the total number of C atoms of R 1 and R 2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)-C8-20alkynyl, - C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R 1 and each instance of R 2 is independently selected from -C 1-20 alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-;
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R 1 and each instance of R 2 is independently selected from -C 1-20 alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C 1-6 alkylene-, -C 2-6 alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-;
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)-C8-20alkynyl, - C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-;
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C 2-20 alkenyl, -OC(O)-C 2-20 alkynyl, -C(O)O-C 1-20 alkyl, -C(O)O-C 2-20 alkenyl, and - C(O)O-C
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C 1-20 alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R 1 and each instance of R 2 is independently selected from -H, -C 1-20 alkyl, -C 2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -OC(O)-, and -NR4C(
  • the present invention further provides 2 specific variants of the lipids as defined herein, i.e. those in which the lipid tails are indirectly attached to the -NH- moiety through carboxylic acid- containing linker moieties (represented by formulae IIa, and IIb), and those in which the lipid tail tails are directly attached to the -N- moiety through carboxylic acid-containing linker moieties (represented by formulae IIIa, and IIIb).
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIa), or formula (IIb) wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkeny
  • the present invention provides a lipid, in particular an ionizable 5 lipid as defined herein and being represented by formula (IIa) or (IIb) wherein one or more of the following applies: each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; In particular each instance of X1, each instance of X2, and each instance of X3 is independently -C1-6alkylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 2 0 alkenyl and -C 2-20 alkynyl; wherein each of said -C 1-20 alkyl, -C 2-20 alkenyl and -C 2-20 alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and
  • an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2- 20alkynyl.
  • an ionizable lipid is provided by the present invention, wherein wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1- 6alkylene-.
  • an ionizable lipid is provided by the present invention, wherein each instance of X 1 , each instance of X2, and each instance of X3 is independently selected from -C1-6alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, and -C2-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1-6alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, and -C2- 20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C8-20alkyl, and -C8-20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X1, each instance of X 2 , and each instance of X 3 is independently selected from -C 1-6 alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C8-20alkyl, and -C8- 20alkenyl.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIa), or formula (IIIb) each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; -C2- 20alkenylene-; and -C2-20alkynylene-; each instance of R6 and each instance of R6 is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alky
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIa) or (IIIb) wherein one or more of the following applies: each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-, -C2- 20alkenylene-, and -C2-20alkynylene-; In particular each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; More in particular each instance of X4 and each instance of X5 is independently selected from -C1-8alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; In particular each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2-20alkenyl; More in particular each instance of R6 and
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of R6 and each instance of R 6’ is independently selected from -C 1-20 alkyl, and -C 2-20 alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2- 2 0 alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2- 20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, and -C8- 20alkenyl.
  • an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R 6 and each instance of R 6’ is independently selected from -C 8-20 alkyl, and -C 8- 20alkenyl.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IVa), formula (IVb), formula (IVc), formula (IVd), or formula (IVe)
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Va), formula (Va’), formula (Vb), formula (Vb’), formula (Vc), formula (Vd), formula (Vd’), or formula (Ve) 5 wherein Z, R1, R2, and R7 are as defined in any one of the embodiments of the present invention.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VaN), formula (Va’N), formula (VbN), formula (Vb’N), formula (VcN), formula (VdN), formula (Vd’N), or formula (VeN) 5
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VIa), formula (VIa’), formula (VIb), formula (VIb’), formula (VIc), formula (VId), formula (VId’), or formula (VIe)
  • each instance of Z is independently selected from -C1-12alkylene-, -C2-12alkenylene-, -C2- 12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O-)x, and -(CH2- CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; and R1, and R2 are as defined in any one of the embodiments of the present invention.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VIaN), formula (VIa’N), formula (VIbN), formula (VIb’N), formula (VIcN), formula (VIdN), formula (VId’N), or formula (VIeN)
  • each instance of Z is independently selected from -C1-12alkylene-, -C2-12alkenylene-, -C2- 12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O-)x, and -(CH2- CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; and R1, and R2 are as defined in any one of the embodiments of the present invention.
  • the present invention provides a lipid, in particular an ionizable lipid as defined herein and being selected from the list comprising: In a more specific embodiment, the present invention provides a compound selected from any of the tables disclosed herein. In a further aspect, the present invention provides a lipid nanoparticle or lipid nanoparticle composition comprising a lipid, in particular an ionizable lipid as defined herein.
  • nanoparticle refers to any particle having a diameter making the particle suitable for systemic, in particular intravenous administration, of active agents typically having a diameter of less than 1000 nanometers (nm), preferably less than 500 nm, even more preferably less than 200 nm, such as for example between 50 and 200 nm; preferably between 80 and 160 nm.
  • the nanoparticle of the present invention may be in the form of a lipid nanoparticle or lipid nanoparticle composition comprising a lipid, in particular an ionizable lipid as defined herein.
  • lipid nanoparticle also termed solid lipid nanoparticles (SLNP)
  • LNP solid lipid nanoparticles
  • a lipid nanoparticle is typically spherical with an average diameter between 10 and 1000 nanometers and possesses a lipid core matrix that can solubilize lipophilic molecules.
  • lipid is used here in a broader sense and includes triglycerides, diglycerides, monoglycerides, fatty acids, steroids (e.g. cholesterol) and waxes.
  • the nanoparticles as disclosed herein further comprise one or more additional lipids either or not acting as stabilizers, such as helper lipids (e.g. a phospholipid), a sterol and/or a stabilizer lipids (such as PEGylated lipids).
  • helper lipids e.g. a phospholipid
  • sterol e.g. a sterol
  • stabilizer lipids such as PEGylated lipids
  • the nanoparticles of the present invention may be in any other suitable form such as in the form of a liposome, a lipid nanoemulsion (LNE), a nanostructured lipid carrier (NLC), a hybrid lipid-polymeric nanoparticle, or a hybrid lipid-metal nanoparticle.
  • a liposome is a nanoparticle in the form of a lipid bilayer structure.
  • Such liposomes are typically composed of phospholipids and cholesterol, and are in the present invention combined with one or more ionizable lipids as defined herein.
  • LNEs consist of submicron sized lipid droplets, stabilized by surfactants in an aqueous solution.
  • LNEs for medical use mostly consist of plant-based lipid droplets stabilized by other lipids such as phospholipids and/or ionizable lipids.
  • NLCs are regarded as an alternative SLNP in which solid lipid components are replaced by liquid lipids, thereby resulting in a larger loading capacity for active agents.
  • Hybrid LNPs typically consist of a therapeutic-containing polymeric core enveloped by an inner lipid layer and an outer lipid layer, the latter one often containing PEGylated lipids. Due to the characteristics of both lipids and polymers, these hybrid LNPs present great stability, sustained release and high biocompatibility.
  • Hybrid lipid-metal nanoparticles may be obtained by coating metal nanoparticles with lipids, thereby resulting in improved biocompatibility, nanoparticle stability and endocytosis efficiency.
  • Suitable hybrid lipid-metal nanoparticles are for example hybrid lipid-coated silver nanoparticles (lipid-AgNPs), lipid-aluminum nanoparticles, and liposome gold nanoparticles (LiposAu NPs).
  • lipid-AgNPs hybrid lipid-coated silver nanoparticles
  • LiposAu NPs liposome gold nanoparticles
  • PEG lipid or alternatively “PEGylated lipid” is meant to be any suitable lipid modified with a PEG (polyethylene glycol) group.
  • the term “phospholipid” is meant to be a lipid molecule consisting of two hydrophobic fatty acid “tails” and a hydrophilic “head” consisting of a phosphate group.
  • the two components are most often joined together by a glycerol molecule, hence, the phospholipid of the present invention is preferably a glycerol-phospholipid.
  • the phosphate group is often modified with simple organic molecules such as choline (i.e. rendering a phosphocholine) or ethanolamine (i.e. rendering a phosphoethanolamine).
  • the term “sterol”, also known as steroid alcohol, is a subgroup of steroids that occur naturally in plants, animal and fungi, or can be produced by some bacteria.
  • any suitable sterol may be used, such as selected from the list comprising cholesterol, ergosterol, campesterol, oxysterol, antrosterol, desmosterol, nicasterol, sitosterol and stigmasterol; preferably cholesterol.
  • the nanoparticle nanoparticle composition as defined herein further comprises a cargo molecule such as a pharmaceutically active agent (e.g. small molecule) or a biomolecule, such as a peptide, protein or a nucleic acid.
  • the nanoparticles and nanoparticle compositions of the present invention are particularly suitable for the intracellular delivery of their cargo molecules.
  • the present invention provides the use of the nanoparticles and nanoparticle compositions as defined herein for the intracellular delivery of cargo molecules.
  • the nanoparticle or nanoparticle composition as defined herein further comprises an active agent, such as a small molecule, a therapeutic peptide, a therapeutic protein, a nucleic acid, or any combination thereof.
  • the active agent of the present invention is a therapeutic nucleic acid.
  • a “nucleic acid” in the context of the invention may include deoxyribonucleic acid, ribonucleic acid, recombinantly produced and chemically synthesized molecules.
  • a nucleic acid may include DNA, genomic DNA, cDNA, RNA, tRNA, mRNA, small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides, ribozymes, plasmids, immune stimulating nucleic acids, antisense nucleic acids, antagomirs (anti-miRs), miRs, supermiRs, U1 adaptors, and aptamers.
  • a nucleic acid may according to the invention be in the form of a molecule which is single stranded or double stranded and linear or closed covalently to form a circle.
  • a nucleic acid can be employed for introduction into, i.e.
  • RNA relates to a molecule which comprises ribonucleotide residues and preferably being entirely or substantially composed of ribonucleotide residues.
  • “Ribonucleotide” relates to a nucleotide with a hydroxyl group at the 2'-position of a ⁇ - D-ribofuranosyl group.
  • the term includes double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides.
  • Such alterations can include addition of non-nucleotide material, such as to the end(s) of a RNA or internally, for example at one or more nucleotides of the RNA.
  • Nucleotides in RNA molecules can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides.
  • RNA includes and preferably relates to "mRNA” which means “messenger RNA” and relates to a "transcript” which may be produced using DNA as template and encodes a peptide or protein.
  • mRNA typically comprises a 5' untranslated region (5’ -UTR), a protein or peptide coding region and a 3' untranslated region (3'-UTR).
  • mRNA has a limited halftime in cells and in vitro.
  • mRNA is produced by in vitro transcription using a DNA template.
  • the RNA is obtained by in vitro transcription or chemical synthesis.
  • the in vitro transcription methodology is known to the skilled person. For example, there is a variety of in vitro transcription kits commercially available.
  • the present invention provides a pharmaceutical composition comprising one or more nanoparticles as defined herein and a pharmaceutically acceptable agent, such as a carrier, excipient, etc.
  • the present invention also provides the nanoparticles and pharmaceutical compositions according to this invention for use in human or veterinary medicine.
  • the use of the nanoparticles and pharmaceutical compositions according to this invention for human or veterinary medicine is also intended.
  • the invention provides a method for the prophylaxis and treatment of human and veterinary disorders, by administering the nanoparticles or pharmaceutical compositions according to this invention to a subject in need thereof.
  • Such pharmaceutical compositions are particularly suitable in various fields such as prophylactic vaccines, therapeutic vaccines, protein replacement therapies, gene editing, gene silencing, small molecule delivery, etc.
  • the nanoparticles and pharmaceutical compositions as defined herein may be used in the induction of an immune response in a subject by providing to the subject a pharmaceutical composition wherein the active agent is an immunostimulatory oligonucleotide.
  • the invention provides a vaccine comprising one or more nanoparticles according to the present invention.
  • a vaccine as meant herein contains at least one active agent, such as a nucleic acid molecule, e.g. mRNA molecule encoding an antigen to which an adaptive immune response is mounted.
  • This antigen can be present in the format of a weakened or killed form of a microbe, a protein or peptide, or an antigen encoding a nucleic acid, such as a disease-associated antigen for example a tumor antigen.
  • Vaccines can be prophylactic (example: to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen), or therapeutic (example, to actively treat or reduce the symptoms of an ongoing disease).
  • the nanoparticles and pharmaceutical compositions as defined herein may be used in the treatment of a disease or disorder characterized by the overexpression of a polypeptide in a subject by providing to the subject a pharmaceutical composition of the present invention, wherein the active agent is a nucleic acid selected from an siRNA, a microRNA, and an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense oligonucleotide includes a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof.
  • the nucleic acid is a siRNA or miRNA.
  • the nanoparticles and pharmaceutical compositions as defined herein may be used in the treatment of a disease or disorder characterized by underexpression of a polypeptide in a subject by providing to the subject a pharmaceutical composition of the present invention, wherein the active agent is a plasmid that encodes the polypeptide or a functional variant or fragment thereof, such as in the context of protein replacement therapy.
  • the nanoparticles and compositions as defined herein may be used as a transfection agent that includes the compositions or nanoparticles described herein, wherein the composition or nanoparticles include a nucleic acid. The agent, when contacted with cells, can efficiently deliver nucleic acids to the cells.
  • Yet another aspect is a method of delivering a nucleic acid to the interior of a cell, by obtaining or forming a composition or nanoparticles described herein, and contacting the composition or lipid particles with a cell.
  • the present invention provides the nanoparticles and pharmaceutical compositions of the present invention for use in the treatment of cancer or infectious diseases.
  • the ionizable lipids of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • LNP synthesis Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 9 mL/min, 12mL/min or 16 ml/min using the NanoAssemblr Benchtop (Precision Nanosystems).
  • the lipid solution contained a mixture of the ionizable lipid of interest, DSPC (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti).
  • LNPs were dialyzed against TBS (10000 times more TBS volume than LNP volume) using slide-a-lyzer dialysis cassettes (20K MWCO, 3mL, ThermoFisher).
  • MC3 is an ionizable lipid considered to be known in the state-of-the art and was used as a control.
  • the apparent pKa of formulated LNPs was determined via TNS binding assay as described bu Sabnis et al. (Molecular Therapy, Vol.26, No 6, 2018). Cell lines The most optimal culturing conditions per cell type including growth medium, subcultivation ratio, and medium renewal recommendations are summarized below.
  • OptiMEM serum reduced, Gibco
  • eGFP mRNA and LNPs encapsulating eGFP mRNA were diluted in OptiMEM to get to a concentration of the mRNA content of 200 and 50ng/well.
  • mRNA : lipid complexes were incubated in a 1 : 1 ratio for 5 minutes and were added to each condition in quadruplicate. Cells were incubated for 24 hours at 37°C 5% CO2.
  • eGFP expression For assessment of eGFP expression, cells were stained with SYTOX blue. Within the gate of SYTOX blue negative cells, expression levels of eGFP were determined. The relative mean fluorescence intensity (rel MFI) was calculated as the MFI value of the expression marker divided by that of untransfected cells.
  • Example 2a LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5.
  • eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6.
  • a list of relevant physico-chemical properties for different LNP compositions, based on IL12, IL13, IL14, and MC3 is shown below in Table 1.
  • Figure 1 shows that LNPs containing ionizable lipids according to the invention may show to have no significant impact on the viability of the transfected HEK-293T cells.
  • Figure 2 shows the Relative Mean Fluorescence Intensity (measured as the fold-increase in eGFP MFI compared to untreated cells) of eGFP expression in HEK-293T cells upon incubation with the indicated LNPs at mRNA concentration of 50 ng and 200 ng/well.
  • LNPs containing ionizable lipids according to the invention may be capable of efficiently transfecting HEK 293T cells in a manner that is similar or outperforms that of the control MC3.
  • Table 1 Physico-chemical characteristics of LNPs
  • LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5.
  • eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6.
  • Figure 4 shows the Relative Mean Fluorescence Intensity (measured as the fold-increase in eGFP MFI compared to untreated cells) of eGFP expression in HeK-293T cells upon incubation with the indicated LNPs at mRNA concentration of 50 ng and 200 ng/well.
  • LNPs containing ionizable lipids according to the invention may reach a comparable level of eGFP expression or may outperform the MC3 control.
  • mice were housed in IVC under specific pathogen-free conditions. All animal experiments were performed with approval from the Ethical Committee and animal care was according to established guidelines. Female Balb/C 6-weeks old (20-23g) were obtained from Charles River International Laboratories, Inc. (France) and housed (max 5 per cage) with free access to water and standard laboratory animal chow.
  • mice For intravenous injection, mice are either placed in a warming chamber for vein dilation for no more than 10 min or the cage was placed under a red lamp for 10-20 min. When appropriately warm, mice were restrained individually. The tail was swabbed with gauze dampened in 70% ethanol. The needle of a BD microfine syringe (20-25G) with LNP solution was carefully inserted into one of the side tail veins and applying slow pressure to the plunger a maximum volume of 1 OOpL (for mice of 20-25g) was injected. The needle was removed from the vein and the local bleeding stopped by applying slight pressure to the puncture site with dry gauze. Animals were subsequently observed for at least 10 minutes in their cage. Each injection was equivalent to 10 pg Flue mRNA.
  • Imaging was performed 24h after IV injection of LNP formulations. Each mouse was injected i.p. with 100 pl D-luciferin (30 mg/mL,). Mice were then placed in an anesthesia induction chamber with oxygen supply (0.4-0.8 L/min) and isoflurane (5%) until they undergo narcosis. The flow of isoflurane was then reduced (3%) to maintain narcosis until mice are ready to be imaged. Mice are placed in a maximum of 3 per group in a stage inside the I VIS Lumina II (PerkinElmer) using the same anesthesia flow (3-4% Isoflurane). Imaging is performed with the parameters set to Luminescence, auto exposure with background overlay and medium binning (4), using field of view D.
  • mRNA synthesis FireFly luciferase (Fluc) mRNA was produced from a linearized peTheRNA vector using eTheRNA-optimized in vitro transcription (IVT) reaction conditions and purified via cellulose.
  • Uridine was fully substituted by N1-Methylpseudouridine (N1 ⁇ ) to generate N1 ⁇ -modified mRNA.
  • LNP production Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 12mL/min or 16 ml/min using the NanoAssemblr Benchtop (Precision Nanosystems).
  • the lipid solution contained a mixture of the ionizable lipid of interest, DSPC or DOPE (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti).
  • LNPs were produced at a standard molar ratio ionizable lipid/DSPC or DOPE/cholesterol/DMG- PEG2000 of about 50/10/38.5/1.5.
  • eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6.
  • a list of relevant physico-chemical properties for different LNP compositions, based on IL14, IL19, IL20, IL21, IL25, IL27 and IL28 and MC3 is shown below in Table 3.
  • Table 3. Physico-chemical characteristics of LNPs Ionizable Composition Ratio [mol %] Size [nm] PDI EE% Lipid Figure 5 reveals the in vivo average radiance (normalized in function of photons/second/cm 2 /steradian) as captured by the IVIS.
  • LNPs containing ionizable lipids according to the invention may be similar in terms of average radiance as compared to MC3 based LNPs.
  • Figure 6 displays the ex vivo average radiance of the excised organs, more specifically the liver, spleen and inguinal lymph node.
  • LNPs containing ionizable lipids according to the invention may have a similar performance to MC3.
  • EXAMPLE 4 IN VIVO EXPERIMENTS hEPO expression repeated IV administration of hEPO mRNA containing LNPs
  • mice were housed in IVC under specific pathogen-free conditions. All animal experiments were performed with approval from the Ethical Committee for Animal Experiments and animal care was according to established guidelines. Female Balb/C 6-weeks old (20-23g) were obtained from Charles River International Laboratories, Inc. (France) and housed (max 5 per cage) with free access to water and standard laboratory animal chow.
  • mice For intravenous injection, mice are either placed in a warming chamber for vein dilation for no more than 10 min or the cage was placed under a red lamp for 10-20 min. When appropriately warm, mice were restrained individually. The tail was swabbed with gauze dampened in 70% ethanol. The needle of a BD microfine syringe (20-25G) with LNP solution was carefully inserted into one of the side tail veins and applying slow pressure to the plunger a maximum volume of 100 ⁇ L (for mice of 20-25g) was injected. The needle was removed from the vein and the local bleeding stopped by applying slight pressure to the puncture site with dry gauze. Animals were subsequently observed for at least 10 minutes in their cage.
  • hEPO Human erythropoietin
  • mRNA was produced from a linearized peTheRNA vector using eTheRNA-optimized in vitro transcription (IVT) reaction conditions and purified via cellulose.
  • Uridine was fully substituted by N1-Methylpseudouridine (N1 ⁇ ) to generate N1 ⁇ -modified mRNA.
  • LNP production Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 12mL/min using the NanoAssemblr Benchtop (Precision Nanosystems).
  • the lipid solution contained a mixture of the ionizable lipid of interest, DSPC (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti).
  • LNPs were dialyzed against TBS (10000 times more TBS volume than LNP volume) using slide- a-lyzer dialysis cassettes (20K MWCO, 3mL, ThermoFisher). Size, polydispersity and zeta potential were measured with a Zetasizer Nano (Malvern). mRNA encapsulation was measured by standard Ribogreen RNA assay (Invitrogen).
  • LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5. Fluc mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6.
  • Table 4 Physico-chemical characteristics of LNPs Timepoints Composition Ratio [mol %] Size [nm] PDI EE% T0 7951 0102 94 g g j p as mIU/mL. As shown, expression of hEPO may not affected by repeated administration of an LNP containing an ionizable lipid according to the invention.

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Abstract

The present invention generally relates to the field of ionizable (also termed cationic) lipids, and in particular provides a novel type of such lipids as represented by formula (I). The present invention further provides methods for making such lipids as well as uses thereof, in particular in the preparation of nanoparticle compositions, more in particular nanoparticle compositions comprising nucleic acids. It further provides pharmaceutical formulations comprising nanoparticle compositions based on the ionizable lipids disclosed herein.

Description

IONIZABLE LIPIDS
FIELD OF THE INVENTION
The present invention generally relates to the field of lipids, in particular ionizable (also termed cationic) lipids, and in particular provides a novel type of such lipids as represented by any of the formulae disclosed herein. The present invention further provides methods for making such lipids as well as uses thereof, in particular in the preparation of nanoparticle compositions, more in particular nanoparticle compositions comprising nucleic acids. It further provides pharmaceutical formulations comprising nanoparticle compositions based on the ionizable lipids disclosed herein.
BACKGROUND TO THE INVENTION
Nanoparticles, such as liposomes and lipid nanoparticles are increasingly being used in therapeutic areas for the delivery of active agents, such as small molecules, proteins, nucleic acids, etc. to cells. One of the main requirements for medical use of nanoparticles is that they need to combine efficient and stable encapsulation of the active agents upon storage and in the extracellular environment, with maximum cellular uptake and efficient release of their payload into the cells.
Lipid nanoparticles comprising combinations of cationic lipids with other lipid components have been used to facilitate such cellular uptake of active agents. For example, lipid-based nanoparticles are typically composed of a cationic or ionizable lipid that can be protonated at acid pH, a helper lipid (e.g. phospholipid), a stabilizing lipid (e.g. PEGylated lipid) and a sterol, and have been used in the delivery of nucleic acids.
Each component of a nanoparticle has specialized functions in stability and activity of the nanoparticles. Therefore, further improvements in cationic or ionizable lipid chemistries are needed to improve efficacy and safety of nanoparticle delivered active agents.
Accordingly, the present invention relates to a new class of ionizable lipids as defined by the present set of claims, which have improved characteristics over the currently available classes of ionizable lipids.
SUMMARY OF THE INVENTION In a first aspect, the present invention provides a lipid, in particular an ionizable lipid represented by formula (I)
Figure imgf000003_0001
n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and NRaC(O)NRa; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I) (I)
Figure imgf000005_0001
n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O-5 )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I)
Figure imgf000007_0001
0 n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally an independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I)
Figure imgf000009_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid being represented by formula (I)
Figure imgf000010_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, and -C1-12alkylene-; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In a particular embodiment, the present invention provides a lipid, in particular an ionizable lipid being represented by formula (Ia)
Figure imgf000012_0001
m is an integer selected from 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl. In a more specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIa), or formula (IIb)
Figure imgf000013_0001
Figure imgf000014_0001
wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X1, X2, X3, R5 and R5’, the total number of C atoms of in X1, X2, X3, R5 and R5’ together with the N atom to which they are attached, is at least 5; and wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined herein. In another specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIa), or formula (IIIb)
Figure imgf000014_0002
Figure imgf000015_0001
wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 5 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X4, X5, R6 and R6’, the total number of C atoms of in X4, X5, R6 and R6’ together with the N atom to which they are attached, is at least 6; and wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined herein. In a more particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIb)
Figure imgf000015_0002
wherein n is 1: m is 3; each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, -C8- 20alkenyl and -C8-20alkynyl; wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined herein. In a more specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Va), formula (VaN), formula (Va’), formula (Va’N), formula (Vb), formula (VbN), formula (Vb’), formula (Vb’N), formula (Vc), formula (VcN), formula (Vd), formula (VdN), formula (Vd’), formula (Vd’N), formula (Ve) or formula (VeN)
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
wherein Z, R1, R2, and 7 are as defined herein.
In particular, the present invention provides an ionizable lipid represented by formula (VII)
Figure imgf000019_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein the total number of C atoms in R1 and R2 together is at least 8; each instance of Y1 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of Y2 is independently selected from -O-, and -NR4-; each instance of B1 is independently selected from =O, and =S; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In particular, the present invention provides an ionizable lipid represented by formula (VIIIa), or formula (VIIIb)
Figure imgf000020_0001
wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein the total number of C atoms in X1, X2, X3, R5 and R5’ together is at least 5; and wherein Y1, Y2, Z, B1, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention. In particular, the present invention provides an ionizable lipid represented by formula (IXa), or formula (IXb)
Figure imgf000021_0001
wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-, -C2- 20alkenylene-, and -C2-20alkynylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein the total number of C atoms in X4, X5, R6 and R6’ together is at least 6; wherein Y1, Y2, Z, B1, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention. In particular, the present invention provides an ionizable lipid represented by formula (Xa), formula (Xb), formula (Xc), formula (Xd), or formula (Xe)
Figure imgf000021_0002
Figure imgf000022_0001
wherein Y1, Y2, Z, B1, R1, R2, R3, R4, R4, and m are as defined any one of the embodiments of the present invention. In particular, the present invention provides an ionizable lipid wherein n is 1. In particular, the present invention provides an ionizable lipid wherein m is an integer selected from 1, 2, and 3. In particular, the present invention provides an ionizable lipid wherein each instance of R1 and each instance of R2 is independently selected from -H, and -C1-8alkyl; wherein each of said -C1- 8alkyl is independently substituted with from 1 to 3 substituents independently selected from - OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; and wherein the total number of C atoms in R1 and R2 together is at least 8. In particular, the present invention provides an ionizable lipid wherein each instance of Y1 is independently selected from a direct bond, and -CH2-. In particular, the present invention provides an ionizable lipid wherein each instance of Y2 is independently selected from -O-. In particular, the present invention provides an ionizable lipid wherein each instance of B1 is independently =O. In particular, the present invention provides an ionizable lipid wherein each instance of Z is independently selected from -C1-3alkylene-. In particular, the present invention provides an ionizable lipid wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. In a further embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being selected from the list comprising:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
In a further aspect, the present invention provides a lipid nanoparticle or lipid nanoparticle composition comprising a lipid, in particular an ionizable lipid as defined herein. Said nanoparticle composition may further comprise additional lipids either or not acting as stabilizers, such as a phospholipid, a sterol and/or a PEG lipid.
In yet a further embodiment, the lipid nanoparticle or lipid nanoparticle composition as defined herein further comprises an active agent, in particular a nucleic acid, preferably mRNA. In a further aspect, the present invention provides the use of a lipid, in particular an ionizable lipid as defined herein in the manufacture of a lipid nanoparticle or lipid nanoparticle composition. In a further aspect, the present invention provides a lipid, in particular an ionizable lipid represented by formula (I)
Figure imgf000030_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In a final aspect, the present invention provides a pharmaceutical composition comprising one or more nanoparticles as defined herein and a pharmaceutically acceptable agent, such as a carrier, excipient, etc. Such pharmaceutical compositions are particularly suitable in various fields such as prophylactic vaccines, therapeutic vaccines, protein replacement therapies, gene editing, gene silencing, small molecule delivery, etc. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 (FIG.1) shows a representation of the viability of HEK 293T cells after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations. Figure 2 (FIG.2) shows a representation of the relative Mean Fluorescence Intensity (MFI) in HEK 293T cells of eGFP after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations. Figure 3 (FIG.3) shows a representation of the viability of HEK 293T cells after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations. Figure 4 (FIG.4) shows a representation of the relative Mean Fluorescence Intensity (MFI) in HEK 293T cells of eGFP after 24 h incubation with 50 ng or 200 ng/well of respective LNP formulations. Figure 5 (FIG.5) shows a representation of the Average Radiance measured in vivo (supine view) for different LNP formulations containing Fluc mRNA. Figure 6 (FIG.6) shows a representation of the Average Radiance measured ex vivo for different LNP formulations containing Fluc mRNA. Figure 7 (FIG. 7) shows a representation of the average hEPO levels measured in blood at different timepoints 24 h post injection. The three injections were administered with a weekly interval. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part. As already mentioned herein before, in a first aspect, the present invention provides a lipid, in particular an ionizable lipid represented by formula (I)
Figure imgf000033_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, -5 OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. When describing the compounds/lipids of the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise: The term "alkyl" by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula CxH2x+1 wherein x is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 20 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C1-4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. n-butyl, i-butyl and t- butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, tridecyl and its isomers, tetradecyl and its isomers, pentadecyl and its isomers, hexadecyl and its isomers, heptadecyl and its isomers, octadecyl and its isomers, nonadecyl and its isomers, eicosanyl and its isomers. The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3, or 4 substituents) at any available point of attachment. Non-limiting examples of such substituents include esters, carboxylic acids, alkyl moieties, alkene moieties, alkyne moieties, … and the like. When referring to an alkyl group, for example -C1-6alkyl, being optionally substituted, it also refers to groups comprising said alkyl group, for example -O-C1-6alkyl, -OC(O) -C1-6alkyl, -C(O)O-C1-6alkyl, and the like. In the context of the present invention, the alkyl, alkenyl and alkynyl moieties as defined herein may also further comprise one or more heteroatoms, such as selected from N, S or O, in that for example a carbon atom in an alkyl, alkene or alkyne chain is replaced by a heteroatom. When two or more C atoms are replaced by heteroatoms, the heteroatoms may be adjacent or separated, as long as it results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. An example of a stable combination of two adjacent heteroatoms is a disulfide (-S-S-) group. Where a carbon atom in an alkyl, alkenyl or alkynyl chain is replaced by an N atom, the N atom may be N or NH depending on the number of bonds connected to said C atom. The term "alkenyl" or “alkene”, as used herein, unless otherwise indicated, means straight-chain, cyclic, or branched-chain hydrocarbon radicals containing at least one carbon-carbon double bond. Examples of alkenyl radicals include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, be it in the terminal or internal positions and the like. Generally alkenyl or alkene moieties of the present invention comprise from 2 to 20 C atoms. An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl. The term "alkynyl", as used herein, unless otherwise indicated, means straight-chain or branched-chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl, hexynyl, hexadiynyl, be it in the terminal or internal positions, and the like. An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl. The term “cycloalkyl” by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1, 2, or 3 cyclic structure. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 15 atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl and cyclodecyl with cyclopropyl being particularly preferred. An “optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, for example 1, 2, 3 or 4 substituents), selected from those defined above for substituted alkyl. Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene" and "alkynylene" respectively. The term "heterocycle" as used herein by itself or as part of another group refers to non- aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl. Non-limiting examples of heterocycle comprise: piperidinyl, azepanyl, morpholinyl. The term “aryl" (herein also referred to as aromatic heterocycle) as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene) or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, …. The aryl ring or heterocycle as defined herein can optionally be substituted by one or more substituents (for example 1 to 5 substituents, for example 1, 2, 3 or 4) at any available point of attachment. Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO2-NH2, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO2Ra, alkylthio, carboxyl, and the like, wherein Ra is alkyl or cycloalkyl. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring. The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: piridinyl, azepinyl,… An “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1, 2, 3 or 4), selected from those defined above for substituted aryl. The term “oxo” as used herein refers to the group =O. The term “alkoxy" or “alkyloxy” as used herein refers to a radical having the Formula -ORx wherein Rx is alkyl. Preferably, alkoxy is C1-C10 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy. Non- limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Where the oxygen atom in an alkoxy group is substituted with sulfur, the resultant radical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy; trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy. The term "carboxy" or “carboxyl” or “hydroxycarbonyl” by itself or as part of another substituent refers to the group -CO2H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -CO2H. The term "alkoxycarbonyl" by itself or as part of another substituent refers to a carboxy group linked to an alkyl radical i.e. to form -C(O)ORe, wherein Re is as defined above for alkyl. The term “alkylcarbonyloxy” by itself or as part of another substituent refers to a -O-C(O)Re wherein Re is as defined above for alkyl. Whenever the term “substituted” is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. Where groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice. Substituents may be selected from, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano, haloalkoxy, and haloalkyl. As used herein the terms such as “alkyl, aryl, or cycloalkyl, each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl. In the context of the present invention, the term lipid is meant to be a chemically defined substance that is insoluble in water but soluble in amongst others alcohol, ether and chloroform. Ionizable or cationic lipids are lipids that are typically composed of three sections: an amine head group, a linker moiety and a hydrophobic tail. The term “ionizable” (or alternatively cationic) in the context of a compound or lipid means the presence of any uncharged group in said compound or lipid which is capable of dissociating by yielding an ion (usually an H+ ion) and thus itself becoming positively charged. Alternatively, any uncharged group in said compound or lipid may yield an electron and thus becoming negatively charged. All of the lipids as defined herein may occur as different isomers/stereomers. In particular, the lipids as defined herein may occur in the trans or cis configuration, such as when they contain double bonds. In a preferred embodiment, the lipids as defined herein occur in the cis configuration. In the context of the present invention, the term ‘cis’ indicates that the functional groups are on the same side of a plane, whereas ‘trans’ means that they are on opposite sides. As used herein, when a compound has one or more stereocenters, each stereocenter may have the R or S configuration, unless stated otherwise. The compound may therefore be a racemic mixture of enantiomers and/or diastereoisomers, or it may have an excess of one or more of the enantiomers and/or diastereoisomers, such as more than 60 %, more than 70 %, more than 80 %, more than 85 %, more than 90 %, more than 95 %, more than 98 %, more than 99 %. This new class of ionizable lipids, having improved characteristics over the currently available classes of ionizable lipids, was inspired to be metabolizable (back) into Vitamin B derivatives (e.g. pyridoxine, pyridoxamine, pyridoxal) and/or other benign fragments. In specific embodiments of the invention, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I) wherein one or more of the following applies: n is an integer selected from 1, 2, and 3; In particular n is an integer selected from 1, and 2; More in particular n is 1; m is an integer selected from 0, 1, 2, 3, and 4; In particular m is an integer selected from 1, 2, 3, and 4; More in particular m is an integer selected from 1, 2, and 3; Even more in particular m is 3; wherein the sum of n and m is at least 4; In particular wherein the sum of n and m is 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; In particular each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl, optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; More in particular each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl; Even more in particular each instance of R1 is independently selected from -H, and -C1- 20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, - C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; In particular each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl, optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; More in particular each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl; Even more in particular each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; In particular wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is from 10 to 30; More in particular wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is from 12 to 28; Even more in particular wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is from 14 to 26; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; In particular each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; In particular each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; More In particular each instance of R7 is independently selected from -C1-20alkyl, and - C2-20alkenyl; Even more In particular each instance of R7 is independently selected from -C8-20alkyl, and -C8-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; In particular each instance of Y is independently selected from a direct bond, -C1- 6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; More in particular each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; In particular each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, - OC(O)O-, -NRaC(O)-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; More In particular each instance of FG is independently selected from -O-, -NRa-, - OC(O)-, -NRaC(O)-, -NRaC(O)O-, and -OC(O)NRa-; Even more In particular each instance of FG is independently selected from -OC(O)-, and -NRaC(O)-; each instance of Ra is independently selected from -H, and -C1-6alkyl; In particular each instance of Ra is independently selected from -H, and -CH3; More in particular each instance of Ra is -H; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; In particular each instance of Z is independently selected from a direct bond, -C1- 12alkylene-, -C2-12alkenylene-, and -C2-12alkynylene; wherein each of said -C1-12alkylene- , -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and - O-C1-6alkyl; More in particular each instance of Z is independently selected from a direct bond, and -C1-12alkylene-; wherein each of said -C1-12alkylene-optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from - halo, -OH, and -O-C1-6alkyl; Yet even more in particular each instance of Z is independently selected from -C1- 12alkylene-; Yet even more in particular each instance of Z is independently selected from -C1- 6alkylene-; Yet even more in particular each instance of Z is independently selected from -C1- 3alkylene-; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; In particular wherein each instance of x and each instance of y is an integer independently selected from 1 to 5; More in particular wherein each instance of x and each instance of y is an integer independently selected from 1 to 3; Even more in particular wherein each instance of x and each instance of y is an integer independently selected from 1 or 2; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; In particular each instance of R3 is independently selected from -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -OH, -O-C1-6alkyl, -C(O)H, -OC(O)-C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-SH, and -C1-6alkyl-NR4R4’; More in particular each instance of R3 is independently selected from -C1-6alkyl, -OH, - O-C1-6alkyl, -OC(O)-C1-6alkyl, -C1-6alkyl-OH, and -C1-6alkyl-NR4R4’; Even more in particular each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NR4R4’; Yet even more in particular each instance of R3 is independently selected from -CH3, - OH, -CH2-OH, and -CH2-NH2’; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; In particular each instance of R4 and each instance of R4’ is independently selected from -H, -CH3, -CH2-Ph, -C(O)-CH3, and -C(O)O-C(CH3)3; or In particular each instance of R4 and each instance of R4’ taken together with the N atom to which they are attached forms a 5-7 membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1- 6alkyl-OH; More in particular each instance of R4 and each instance of R4’ taken together with the N atom to which they are attached forms a 5-7 membered non-aromatic heterocycle; said heterocycle being selected from pyrrolidine, piperidine, azepine, and piperazine; Even more in particular each instance of R4 and each instance of R4’ taken together with the N atom to which they are attached forms a 5-7 membered non-aromatic heterocycle; said heterocycle being azepine. each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; In particular each instance of Cy1 is independently a 5- to 7-membered non-aromatic cycle comprising at least 1 N atom, optionally and independently comprising 1 to 4 additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; More in particular each instance of Cy1 is independently selected from pyrrolidine, piperidine, piperazine, and azepine, optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, - NRbRb’, and -C1-6alkyl-NRbRb’; Even more in particular each instance of Cy1 is independently selected from pyrrolidine, piperidine, piperazine, and azepine; or In particular each instance of Cy1 is independently a 5- to 10-membered aromatic cycle comprising at least 1 N atom, optionally and independently comprising 1 to 4 additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; More in particular each instance of Cy1 is independently a 5- to 6-membered aromatic cycle comprising at least 1 N atom, optionally and independently comprising 1 to 4 additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, - C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; Even more in particular each instance of Cy1 is independently selected from pyrrole, imidazole, pyrazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, oxazine, and thiazine, optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl- NRbRb’; Yet even more in particular each instance of Cy1 is independently selected from pyrrole, imidazole, pyrazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, oxazine, and thiazine; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; In particular each instance of Het1 is independently a 5- to 7-membered non-aromatic heterocycle comprising at least 1 N atom, optionally and independently comprising 1 to 3 additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; More in particular each instance of Het1 is independently selected from pyrrolidine, piperidine, piperazine, and azepine, optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH; Even more in particular each instance of Het1 is independently selected from pyrrolidine, piperidine, piperazine, and azepine; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; In particular each instance of Ar1 is independently selected from phenyl, pyrrole, imidazole, pyrazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, oxazine, and thiazine, optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl- NRbRb’; In particular each instance of Ar1 is independently phenyl, optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -C1-6alkyl, - C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; More in particular each instance of Ar1 is independently phenyl; each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In particular each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; and More in particular each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and -Bn; In particular, an ionizable lipid is provided by the present invention, wherein the sum of n and m is at least 4, such as 4 or 5. In specific embodiments of the invention, the sum of n and m is 4. In specific embodiments of the invention, n is an integer selected from 1, and 2. In preferred embodiments of the invention, n is 1. In an alternative embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia);
Figure imgf000045_0001
wherein m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. In specific embodiments of the invention, m is an integer selected from 1, 2, 3, and 4. In other specific embodiments of the invention, m is an integer selected from 2, 3, and 4. In preferred embodiments of the invention, m is 3. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R2 5 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R7 is independently selected from -C1-20alkyl, and -C2-20alkenyl; wherein each of said -C1-20alkyl, and -C2-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; and each instance of R7 is independently selected from -C1-20alkyl, and -C2-20alkenyl; wherein each of said -C1-20alkyl, and -C2-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R7 is independently selected from -C8-20a y, a d C8-20alkenyl; wherein each of said -C8-20alkyl, and -C8-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents; In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -OC(O)-R7, and -C(O)O-R7; and each instance of R7 is independently selected from -C8-20alkyl, and -C8-20alkenyl; wherein each of said -C8-20alkyl, and -C8-20alkenyl is optionally and independently substituted with from 1 to 3 -OH substituents; In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2- 20alkenyl; and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is independently selected from -H, and -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8- 20alkenyl; and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said - C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C1-20alkyl, and -C(O)O-C2-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein an ionizable lipid is provided as defined herein, wherein each instance of R1 and each instance of R2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -C(O)O-C1-20alkyl, and -C(O)O-C2- 20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 and each instance of R2 is independently selected from -C1-12alkyl; wherein each of said -C1-12alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R1 is -H; and each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7. In particular, an ionizable lipid is provided by the present invention, wherein each instance of Y is independently selected from a direct bond, and -CH2-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, -NRaC(O)O-, and - OC(O)NRa-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of FG is independently selected from -OC(O)-, and -NRaC(O)-. In even more specific embodiments of the invention, an ionizable lipid is provided as defined herein, wherein each instance of FG is independently selected from -OC(O)-, and -NHC(O)- . In particular, an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, and -C2-12alkynylene; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from a direct bond, and C1-12alkylene-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of Z is independently selected from -C1-12alkylene-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. In a particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia);
Figure imgf000052_0001
wherein m is an integer selected from 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; and each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. In a more particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Ia);
Figure imgf000053_0001
wherein m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O- C8-20alkyl, and -C(O)O-C8-20alkenyl. wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of Y is independently selected from a direct bond, and -CH2-; 5 each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, and -C1-12alkylene-; and each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. In a particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independe ty substtuted ith from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-20alkyl; wherein each of said -C1-20alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -OC(O)- C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and -C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-20alkyl; wherein each of said -C1-20alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)- C8-20alkynyl, -C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-20alkyl; wherein each of said -C1-20alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)- C8-20alkynyl, -C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 is -H; each instance of R2 is -C1-8alkyl; wherein each of said -C1-8alkyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with 2 substituents independently selected from -OC(O)-C8-20alkyl, and -OC(O)-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, -OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, - C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and -C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)-C8-20alkynyl, - C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-20alkyl; wherein each of said -C1-20alkyl is independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -OC(O)-C8-20alkynyl, - C(O)O-C8-20alkyl, -C(O)O-C8-20alkenyl, and -C(O)O-C8-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and O-C1-6alkyl; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- , and -C2-6alkynylene; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- 5 membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, and -C1-6alkylene-; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from -C1-6alkylene-; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2- 6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl, -NR4R4’, -C(O)-C1- 6alkylene-NR4R4’, -C(O)O-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-NR4R4’; and each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with an aryl substituent; wherein each of said aryl is a 5- to 8- membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents selected from -halo, -C1-6alkyl, -C3-6cycloalkyl, OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NH2; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and -C1-6alkyl-OH. In another particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -H, -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally further comprises one or more heteroatoms and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C1-20alkyl, - OC(O)-C2-20alkenyl, -OC(O)-C2-20alkynyl, -C(O)O-C1-20alkyl, -C(O)O-C2-20alkenyl, and - C(O)O-C2-20alkynyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; and each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. In a more particular embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (I); wherein n is 1; m is an integer selected from 3, and 4; each instance of R1 and each instance of R2 is independently selected from -C1-8alkyl; wherein each of said -C1-8alkyl is independently substituted with from 1 to 3 substituents independently selected from -OC(O)-C8-20alkyl, -OC(O)-C8-20alkenyl, -C(O)O-C8-20alkyl, and -C(O)O-C8-20alkenyl; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -OC(O)-, and -NR4C(O)-; each instance of Z is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- , and -C2-6alkynylene; each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, and -CH2-NH2. The present invention further provides 2 specific variants of the lipids as defined herein, i.e. those in which the lipid tails are indirectly attached to the -NH- moiety through carboxylic acid- containing linker moieties (represented by formulae IIa, and IIb), and those in which the lipid tail tails are directly attached to the -N- moiety through carboxylic acid-containing linker moieties (represented by formulae IIIa, and IIIb). Accordingly, in a specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIa), or formula (IIb)
Figure imgf000072_0001
wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X1, X2, X3, R5 and R5’, the total number of C atoms of in X1, X2, X3, R5 and R5’ together with the N atom to which they are attached, is at least 5; and wherein Y, FG, Z, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention. In another specific embodiment, the present invention provides a lipid, in particular an ionizable 5 lipid as defined herein and being represented by formula (IIa) or (IIb) wherein one or more of the following applies: each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; In particular each instance of X1, each instance of X2, and each instance of X3 is independently -C1-6alkylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from - OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; In particular each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; More in particular each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, and -C2-20alkenyl; Even more in particular each instance of R5 and each instance of R5’ is independently selected from -C8-20alkyl, and -C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2- 20alkynyl. In particular, an ionizable lipid is provided by the present invention, wherein wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1- 6alkylene-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1-6alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, and -C2-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1-6alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, and -C2- 20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R5 and each instance of R5’ is independently selected from -C8-20alkyl, and -C8-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from -C1-6alkylene-; and each instance of R5 and each instance of R5’ is independently selected from -C8-20alkyl, and -C8- 20alkenyl. Accordingly, in a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIa), or formula (IIIb)
Figure imgf000074_0001
each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; -C2- 20alkenylene-; and -C2-20alkynylene-; each instance of R6 and each instance of R6 is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X4, X5, R6 and R6’, the total number of C atoms of in X4, X5, R6 and R6’ together with the N atom to which they are attached, is at least 6; and wherein Y, FG, Z, R3, R4, R4’, n and m are as defined in any one of the embodiments of the present invention. In another specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IIIa) or (IIIb) wherein one or more of the following applies: each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-, -C2- 20alkenylene-, and -C2-20alkynylene-; In particular each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; More in particular each instance of X4 and each instance of X5 is independently selected from -C1-8alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; In particular each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2-20alkenyl; More in particular each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, and -C8-20alkenyl; In particular, an ionizable lipid is provided by the present invention, wherein each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2-20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2- 20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, and -C2- 20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-20alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, and -C8- 20alkenyl. In particular, an ionizable lipid is provided by the present invention, wherein each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; and each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, and -C8- 20alkenyl. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (IVa), formula (IVb), formula (IVc), formula (IVd), or formula (IVe)
5
Figure imgf000077_0001
wherein Y, FG, Z, R1, R2, R3, R4, R4, and m are as defined in any one of the embodiments of the present invention. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (Va), formula (Va’), formula (Vb), formula (Vb’), formula (Vc), formula (Vd), formula (Vd’), or formula (Ve) 5
Figure imgf000078_0001
wherein Z, R1, R2, and R7 are as defined in any one of the embodiments of the present invention. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VaN), formula (Va’N), formula (VbN), formula (Vb’N), formula (VcN), formula (VdN), formula (Vd’N), or formula (VeN) 5
Figure imgf000079_0001
Figure imgf000080_0001
wherein Z, R1, and R2 are as defined in any one of the embodiments of the present invention. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VIa), formula (VIa’), formula (VIb), formula (VIb’), formula (VIc), formula (VId), formula (VId’), or formula (VIe)
Figure imgf000080_0002
Figure imgf000081_0001
wherein each instance of Z is independently selected from -C1-12alkylene-, -C2-12alkenylene-, -C2- 12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O-)x, and -(CH2- CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; and R1, and R2 are as defined in any one of the embodiments of the present invention. In a further specific embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being represented by formula (VIaN), formula (VIa’N), formula (VIbN), formula (VIb’N), formula (VIcN), formula (VIdN), formula (VId’N), or formula (VIeN)
Figure imgf000081_0002
Figure imgf000082_0001
wherein each instance of Z is independently selected from -C1-12alkylene-, -C2-12alkenylene-, -C2- 12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O-)x, and -(CH2- CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2-12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; and R1, and R2 are as defined in any one of the embodiments of the present invention. In a further embodiment, the present invention provides a lipid, in particular an ionizable lipid as defined herein and being selected from the list comprising: In a more specific embodiment, the present invention provides a compound selected from any of the tables disclosed herein. In a further aspect, the present invention provides a lipid nanoparticle or lipid nanoparticle composition comprising a lipid, in particular an ionizable lipid as defined herein. As used herein, the term "nanoparticle" refers to any particle having a diameter making the particle suitable for systemic, in particular intravenous administration, of active agents typically having a diameter of less than 1000 nanometers (nm), preferably less than 500 nm, even more preferably less than 200 nm, such as for example between 50 and 200 nm; preferably between 80 and 160 nm. In a very specific embodiment, the nanoparticle of the present invention may be in the form of a lipid nanoparticle or lipid nanoparticle composition comprising a lipid, in particular an ionizable lipid as defined herein. In the context of the present invention, the term lipid nanoparticle (LNP), also termed solid lipid nanoparticles (SLNP), is meant to be a nanoparticle comprising lipids. They are often used as a pharmaceutical drug delivery system or pharmaceutical formulation. LNPs as drug delivery vehicle were first approved in 2018 and are currently used in several candidate RNA based vaccines. A lipid nanoparticle is typically spherical with an average diameter between 10 and 1000 nanometers and possesses a lipid core matrix that can solubilize lipophilic molecules. The term lipid is used here in a broader sense and includes triglycerides, diglycerides, monoglycerides, fatty acids, steroids (e.g. cholesterol) and waxes. Biological membrane lipids such as phospholipids, sphingomyelins, bile acids and sterols are typically used as stabilizers in LNPs. Accordingly, in the context of the present invention, the nanoparticles as disclosed herein further comprise one or more additional lipids either or not acting as stabilizers, such as helper lipids (e.g. a phospholipid), a sterol and/or a stabilizer lipids (such as PEGylated lipids). Alternatively, the nanoparticles of the present invention may be in any other suitable form such as in the form of a liposome, a lipid nanoemulsion (LNE), a nanostructured lipid carrier (NLC), a hybrid lipid-polymeric nanoparticle, or a hybrid lipid-metal nanoparticle. In the context of the invention, a liposome is a nanoparticle in the form of a lipid bilayer structure. Such liposomes are typically composed of phospholipids and cholesterol, and are in the present invention combined with one or more ionizable lipids as defined herein. LNEs consist of submicron sized lipid droplets, stabilized by surfactants in an aqueous solution. LNEs for medical use mostly consist of plant-based lipid droplets stabilized by other lipids such as phospholipids and/or ionizable lipids. NLCs are regarded as an alternative SLNP in which solid lipid components are replaced by liquid lipids, thereby resulting in a larger loading capacity for active agents. Hybrid LNPs typically consist of a therapeutic-containing polymeric core enveloped by an inner lipid layer and an outer lipid layer, the latter one often containing PEGylated lipids. Due to the characteristics of both lipids and polymers, these hybrid LNPs present great stability, sustained release and high biocompatibility. Hybrid lipid-metal nanoparticles may be obtained by coating metal nanoparticles with lipids, thereby resulting in improved biocompatibility, nanoparticle stability and endocytosis efficiency. Suitable hybrid lipid-metal nanoparticles are for example hybrid lipid-coated silver nanoparticles (lipid-AgNPs), lipid-aluminum nanoparticles, and liposome gold nanoparticles (LiposAu NPs). In the context of the present invention, the term “PEG lipid” or alternatively “PEGylated lipid” is meant to be any suitable lipid modified with a PEG (polyethylene glycol) group. In the context of the present invention, the term “phospholipid” is meant to be a lipid molecule consisting of two hydrophobic fatty acid “tails” and a hydrophilic “head” consisting of a phosphate group. The two components are most often joined together by a glycerol molecule, hence, the phospholipid of the present invention is preferably a glycerol-phospholipid. Furthermore, the phosphate group is often modified with simple organic molecules such as choline (i.e. rendering a phosphocholine) or ethanolamine (i.e. rendering a phosphoethanolamine). In the context of the present invention, the term “sterol”, also known as steroid alcohol, is a subgroup of steroids that occur naturally in plants, animal and fungi, or can be produced by some bacteria. In the context of the present invention, any suitable sterol may be used, such as selected from the list comprising cholesterol, ergosterol, campesterol, oxysterol, antrosterol, desmosterol, nicasterol, sitosterol and stigmasterol; preferably cholesterol. In yet a further embodiment of the present invention, the nanoparticle nanoparticle composition as defined herein further comprises a cargo molecule such as a pharmaceutically active agent (e.g. small molecule) or a biomolecule, such as a peptide, protein or a nucleic acid. Accordingly, the nanoparticles and nanoparticle compositions of the present invention are particularly suitable for the intracellular delivery of their cargo molecules. Hence, the present invention provides the use of the nanoparticles and nanoparticle compositions as defined herein for the intracellular delivery of cargo molecules. In a particular embodiment, the nanoparticle or nanoparticle composition as defined herein further comprises an active agent, such as a small molecule, a therapeutic peptide, a therapeutic protein, a nucleic acid, or any combination thereof. In a particular embodiment, the active agent of the present invention is a therapeutic nucleic acid. A “nucleic acid” in the context of the invention may include deoxyribonucleic acid, ribonucleic acid, recombinantly produced and chemically synthesized molecules. In particular a nucleic acid may include DNA, genomic DNA, cDNA, RNA, tRNA, mRNA, small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides, ribozymes, plasmids, immune stimulating nucleic acids, antisense nucleic acids, antagomirs (anti-miRs), miRs, supermiRs, U1 adaptors, and aptamers. A nucleic acid may according to the invention be in the form of a molecule which is single stranded or double stranded and linear or closed covalently to form a circle. A nucleic acid can be employed for introduction into, i.e. transfection of cells, for example, in the form of RNA which can be prepared by in vitro transcription from a DNA template. The RNA can moreover be modified before application by stabilizing sequences, capping, and/or polyadenylation. In the context of the present invention, the term "RNA" relates to a molecule which comprises ribonucleotide residues and preferably being entirely or substantially composed of ribonucleotide residues. "Ribonucleotide" relates to a nucleotide with a hydroxyl group at the 2'-position of a ^- D-ribofuranosyl group. The term includes double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of a RNA or internally, for example at one or more nucleotides of the RNA. Nucleotides in RNA molecules can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs. Nucleic acids may be comprised in a vector. The term "vector" as used herein includes any vectors known to the skilled person including plasmid vectors, cosmid vectors, phage vectors such as lambda phage, viral vectors such as adenoviral or baculoviral vectors, or artificial chromosome vectors such as bacterial artificial chromosomes (BAC), yeast artificial or analogs of naturally-occurring RNA. According to the present invention, the term "RNA" includes and preferably relates to "mRNA" which means "messenger RNA" and relates to a "transcript" which may be produced using DNA as template and encodes a peptide or protein. mRNA typically comprises a 5' untranslated region (5’ -UTR), a protein or peptide coding region and a 3' untranslated region (3'-UTR). mRNA has a limited halftime in cells and in vitro. Preferably, mRNA is produced by in vitro transcription using a DNA template. In one embodiment of the invention, the RNA is obtained by in vitro transcription or chemical synthesis. The in vitro transcription methodology is known to the skilled person. For example, there is a variety of in vitro transcription kits commercially available. In a further aspect, the present invention provides a pharmaceutical composition comprising one or more nanoparticles as defined herein and a pharmaceutically acceptable agent, such as a carrier, excipient, etc. The present invention also provides the nanoparticles and pharmaceutical compositions according to this invention for use in human or veterinary medicine. The use of the nanoparticles and pharmaceutical compositions according to this invention for human or veterinary medicine is also intended. In addition, the invention provides a method for the prophylaxis and treatment of human and veterinary disorders, by administering the nanoparticles or pharmaceutical compositions according to this invention to a subject in need thereof. Such pharmaceutical compositions are particularly suitable in various fields such as prophylactic vaccines, therapeutic vaccines, protein replacement therapies, gene editing, gene silencing, small molecule delivery,….. In a specific aspect, the nanoparticles and pharmaceutical compositions as defined herein may be used in the induction of an immune response in a subject by providing to the subject a pharmaceutical composition wherein the active agent is an immunostimulatory oligonucleotide. For example, the invention provides a vaccine comprising one or more nanoparticles according to the present invention. To that end, a vaccine as meant herein contains at least one active agent, such as a nucleic acid molecule, e.g. mRNA molecule encoding an antigen to which an adaptive immune response is mounted. This antigen can be present in the format of a weakened or killed form of a microbe, a protein or peptide, or an antigen encoding a nucleic acid, such as a disease-associated antigen for example a tumor antigen. Vaccines can be prophylactic (example: to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen), or therapeutic (example, to actively treat or reduce the symptoms of an ongoing disease). In another aspect, the nanoparticles and pharmaceutical compositions as defined herein may be used in the treatment of a disease or disorder characterized by the overexpression of a polypeptide in a subject by providing to the subject a pharmaceutical composition of the present invention, wherein the active agent is a nucleic acid selected from an siRNA, a microRNA, and an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense oligonucleotide includes a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof. In a preferred embodiment, the nucleic acid is a siRNA or miRNA. In another aspect, the nanoparticles and pharmaceutical compositions as defined herein may be used in the treatment of a disease or disorder characterized by underexpression of a polypeptide in a subject by providing to the subject a pharmaceutical composition of the present invention, wherein the active agent is a plasmid that encodes the polypeptide or a functional variant or fragment thereof, such as in the context of protein replacement therapy. In yet a further aspect, the nanoparticles and compositions as defined herein may be used as a transfection agent that includes the compositions or nanoparticles described herein, wherein the composition or nanoparticles include a nucleic acid. The agent, when contacted with cells, can efficiently deliver nucleic acids to the cells. Yet another aspect is a method of delivering a nucleic acid to the interior of a cell, by obtaining or forming a composition or nanoparticles described herein, and contacting the composition or lipid particles with a cell. In a very specific embodiment, the present invention provides the nanoparticles and pharmaceutical compositions of the present invention for use in the treatment of cancer or infectious diseases. The ionizable lipids of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry. EXAMPLES EXAMPLE 1: PREPARATION OF THE LIPIDS 1. General information Unless otherwise stated, all glassware was oven dried before use and all reactions were carried out under an argon atmosphere using standard Schlenk-techniques. Dry solvents were purchased from Acros Organics or Sigma-Aldrich and used without further purification. All reagents were purchased from commercial sources and were used without further purification unless otherwise stated. Amines were purchased from commercial sources, or prepared according to methods described in WO2022136641. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminum plates coated with Kieselgel F254 with 0.2 mm thickness. Visualization was achieved by ultraviolet light (254 nm) or by staining with potassium permanganate. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck ans co.). Mass spectra were obtained using a Finnigan MAT 8200 (70 eV), an Agilent 5973 (70 eV), using electrospray ionization (ESI) or electron impact ionization (EI). All 1H NMR, 13C NMR NMR were recorded on a BrukerAV-400 in Chloroform-d1 or DMSO- d6. Chemical shifts are given in parts per million (ppm), referenced to tetramethylsilane using the solvent peak as internal standard (CDCl3: 1H = 7.26 ppm, 13C = 77.16 ppm; CD3SOCD3: 1H = 2.50 ppm, 13C = 39.52 ppm). Coupling constants were quoted in Hz.1H NMR splitting patterns were designated as singlet (s), broad (brd), doublet (d), triplet (t), quartet (q), pentet (p), sextet (se), septet (sep), octet (o) or combinations thereof. Splitting patterns that could not be interpreted were designated as multiplet (m). 2. Synthesis of lipids 2.1 General route A for the synthesis of hydrophobic tail fragment 1, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 2.2 General route B for the synthesis of hydrophobic tail fragment 2, wherein R1 ^ R2, is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000089_0001
2.3 General route C for the synthesis of hydrophobic tail fragment 3, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 5
Figure imgf000089_0002
2.4 General route D for the synthesis of hydrophobic tail fragment 4, wherein R1 ≠ R2, is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000089_0003
2.5 General route E for the synthesis of hydrophobic tail fragment 5, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 2.6 G
Figure imgf000090_0001
eneral route F for the synthesis of hydrophobic tail fragment 6, wherein R1 ≠ R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 2.7
Figure imgf000090_0002
General route G for the synthesis of hydrophobic tail fragment 7, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000090_0003
2.8 General route H for the synthesis of hydrophobic tail fragment 8, wherein R1 ≠ R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 2.9 General route I for the synthesis of hydrophobic tail fragments 9 and 11, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl).
2.10 General route J for the synthesis of hydrophobic tail fragments 10 and 12, wherein R1 ≠ R2, is shown below (Alk is alkyl, alkenyl, or alkynyl). 2.11 General route K for the synthesis of hydrophobic tail fragment 13, wherein R1 = R2, is shown below (Alk is alkyl, alkenyl, or alkynyl).
2.12 General route L for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000093_0001
2.13 General route M for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000093_0002
2.14 General route N for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl). 5
Figure imgf000094_0001
2.15 General route O for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000094_0002
2.16 General route P for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000095_0001
2.17 General route Q for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000095_0002
(Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000095_0003
2.19 General route S for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000096_0001
5 2.20 General route T for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000096_0002
2.21 General route U for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000097_0001
2.22 General route V for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000098_0001
5 (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000098_0002
2.24 General route X for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000099_0001
2.25 General route Y for the synthesis of lipids according to formula (I) is shown below (Alk is alkyl, alkenyl, or alkynyl).
Figure imgf000099_0002
EXAMPLE 2: IN VITRO EXPERIMENTS Materials and methods mRNA synthesis mRNA encoding for eGFP was prepared in vitro by T7-mediated transcription from linearized DNA templates (peTheRNAvs3 vector), which incorporates 5’ and 3’ UTRs and a polyA tail. The final mRNA utilizes Cap1 and 100% replacement of uridine with N1-methyl-pseudo-uridine. LNP synthesis Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 9 mL/min, 12mL/min or 16 ml/min using the NanoAssemblr Benchtop (Precision Nanosystems). The lipid solution contained a mixture of the ionizable lipid of interest, DSPC (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti). LNPs were dialyzed against TBS (10000 times more TBS volume than LNP volume) using slide-a-lyzer dialysis cassettes (20K MWCO, 3mL, ThermoFisher). Size, polydispersity and zeta potential were measured with a Zetasizer Nano (Malvern). mRNA encapsulation was measured by standard Ribogreen RNA assay (Invitrogen). MC3 is an ionizable lipid considered to be known in the state-of-the art and was used as a control. The apparent pKa of formulated LNPs was determined via TNS binding assay as described bu Sabnis et al. (Molecular Therapy, Vol.26, No 6, 2018). Cell lines The most optimal culturing conditions per cell type including growth medium, subcultivation ratio, and medium renewal recommendations are summarized below. To harvest adherent cells, used- up growth medium was discarded and cells were rinsed twice with phosphate buffered saline (PBS) (Sigma) before addition of trypsine-EDTA (0.05%) (Gibco, Thermo Fisher Scientific) to loosen the cells. Medium renewal needs to occur every 2 to 3 days, whenever cells reached confluency of approximately 70%. Cell viability was determined using the Vi-Cell XR Cell Viability Analyzer (Beckman Coulter). Cell Description Source Growth medium Subcultivation type ratio
Figure imgf000100_0001
g p y : Foetal Bovine Serum Transfection Cells were plated in a 96-well plate at a density of 3.0-4.0 x10e4 cells/100µl complete growth medium (specific per cell type). Transfection was performed when cells reached 70-90% confluency. The positive control Lipofectamine (MessengerMAX, Invitrogen) was diluted in OptiMEM (serum reduced, Gibco) and incubated for 10 minutes. In the meantime, eGFP mRNA and LNPs encapsulating eGFP mRNA were diluted in OptiMEM to get to a concentration of the mRNA content of 200 and 50ng/well. mRNA : lipid complexes were incubated in a 1 : 1 ratio for 5 minutes and were added to each condition in quadruplicate. Cells were incubated for 24 hours at 37°C 5% CO2. Afterwards cells were harvested using 1 x TrypLE select enzyme (Gibco) and stained with a live/dead marker SYTOX blue (Life Technologies) in FACS buffer (PBS supplemented with 1% bovin serum albumin (BSA) and 0.09% azide (all from Sigma)). Cells were immediately acquired after addition of the live dead marker using the Attune Nxt Flow Cytometer (ThermoFisher Scientific). eGFP expression For assessment of eGFP expression, cells were stained with SYTOX blue. Within the gate of SYTOX blue negative cells, expression levels of eGFP were determined. The relative mean fluorescence intensity (rel MFI) was calculated as the MFI value of the expression marker divided by that of untransfected cells. Data was acquired on an Attune Nxt cytometer and analyzed with Flow Jo Software. Flow cytometric data were analyzed using the Flowjo version 10 software. Example 2a LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5. eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6. A list of relevant physico-chemical properties for different LNP compositions, based on IL12, IL13, IL14, and MC3 is shown below in Table 1. Figure 1 shows that LNPs containing ionizable lipids according to the invention may show to have no significant impact on the viability of the transfected HEK-293T cells. Figure 2 shows the Relative Mean Fluorescence Intensity (measured as the fold-increase in eGFP MFI compared to untreated cells) of eGFP expression in HEK-293T cells upon incubation with the indicated LNPs at mRNA concentration of 50 ng and 200 ng/well. As evident from Figure 2, LNPs containing ionizable lipids according to the invention may be capable of efficiently transfecting HEK 293T cells in a manner that is similar or outperforms that of the control MC3. Table 1. Physico-chemical characteristics of LNPs
Figure imgf000102_0001
Example 2b
LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5. eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6.
A list of relevant physico-chemical properties for different LNP compositions, based on IL14, IL19, IL20, IL21 , IL25, IL27 and IL28 and MC3 is shown below in Table 2. Table 2. Physico-chemical characteristics of LNPs
Figure imgf000102_0002
Figure 3 shows that LNPs containing ionizable lipids according to the invention may show to have no significant impact on the viability of the transfected HEK-293T cells.
Figure 4 shows the Relative Mean Fluorescence Intensity (measured as the fold-increase in eGFP MFI compared to untreated cells) of eGFP expression in HeK-293T cells upon incubation with the indicated LNPs at mRNA concentration of 50 ng and 200 ng/well. As evident from Figure 4, LNPs containing ionizable lipids according to the invention may reach a comparable level of eGFP expression or may outperform the MC3 control.
EXAMPLE 3: IN VIVO EXPERIMENTS
Bioluminescence imaging after IV administration of Flue mRNA containing LNPs
Materials and methods
Animals
Mice were housed in IVC under specific pathogen-free conditions. All animal experiments were performed with approval from the Ethical Committee and animal care was according to established guidelines. Female Balb/C 6-weeks old (20-23g) were obtained from Charles River International Laboratories, Inc. (France) and housed (max 5 per cage) with free access to water and standard laboratory animal chow.
Intravenous injection
For intravenous injection, mice are either placed in a warming chamber for vein dilation for no more than 10 min or the cage was placed under a red lamp for 10-20 min. When appropriately warm, mice were restrained individually. The tail was swabbed with gauze dampened in 70% ethanol. The needle of a BD microfine syringe (20-25G) with LNP solution was carefully inserted into one of the side tail veins and applying slow pressure to the plunger a maximum volume of 1 OOpL (for mice of 20-25g) was injected. The needle was removed from the vein and the local bleeding stopped by applying slight pressure to the puncture site with dry gauze. Animals were subsequently observed for at least 10 minutes in their cage. Each injection was equivalent to 10 pg Flue mRNA.
Luminescence imaging
Imaging was performed 24h after IV injection of LNP formulations. Each mouse was injected i.p. with 100 pl D-luciferin (30 mg/mL,). Mice were then placed in an anesthesia induction chamber with oxygen supply (0.4-0.8 L/min) and isoflurane (5%) until they undergo narcosis. The flow of isoflurane was then reduced (3%) to maintain narcosis until mice are ready to be imaged. Mice are placed in a maximum of 3 per group in a stage inside the I VIS Lumina II (PerkinElmer) using the same anesthesia flow (3-4% Isoflurane). Imaging is performed with the parameters set to Luminescence, auto exposure with background overlay and medium binning (4), using field of view D. Imaging of the animals was performed no longer than 15 min after luciferin injection (peak of the signal). Once in vivo images were taken, the mice were sacrificed by means of cervical dislocation, dissected and imaging of respectively the liver, spleen and inguinal lymph node under similar imaging conditions. mRNA synthesis FireFly luciferase (Fluc) mRNA was produced from a linearized peTheRNA vector using eTheRNA-optimized in vitro transcription (IVT) reaction conditions and purified via cellulose. Uridine was fully substituted by N1-Methylpseudouridine (N1^) to generate N1^-modified mRNA. LNP production Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 12mL/min or 16 ml/min using the NanoAssemblr Benchtop (Precision Nanosystems). The lipid solution contained a mixture of the ionizable lipid of interest, DSPC or DOPE (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti). LNPs were produced at a standard molar ratio ionizable lipid/DSPC or DOPE/cholesterol/DMG- PEG2000 of about 50/10/38.5/1.5. eGFP mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6. A list of relevant physico-chemical properties for different LNP compositions, based on IL14, IL19, IL20, IL21, IL25, IL27 and IL28 and MC3 is shown below in Table 3. Table 3. Physico-chemical characteristics of LNPs Ionizable Composition Ratio [mol %] Size [nm] PDI EE% Lipid
Figure imgf000104_0001
Figure 5 reveals the in vivo average radiance (normalized in function of photons/second/cm2/steradian) as captured by the IVIS. The mice are positioned in a manner that the image is taken in the supine view. As shown in the graph, LNPs containing ionizable lipids according to the invention may be similar in terms of average radiance as compared to MC3 based LNPs.
Figure 6 displays the ex vivo average radiance of the excised organs, more specifically the liver, spleen and inguinal lymph node. There, LNPs containing ionizable lipids according to the invention may have a similar performance to MC3.
EXAMPLE 4: IN VIVO EXPERIMENTS hEPO expression repeated IV administration of hEPO mRNA containing LNPs
Materials and methods:
Animals
Mice were housed in IVC under specific pathogen-free conditions. All animal experiments were performed with approval from the Ethical Committee for Animal Experiments and animal care was according to established guidelines. Female Balb/C 6-weeks old (20-23g) were obtained from Charles River International Laboratories, Inc. (France) and housed (max 5 per cage) with free access to water and standard laboratory animal chow.
Intravenous injection
For intravenous injection, mice are either placed in a warming chamber for vein dilation for no more than 10 min or the cage was placed under a red lamp for 10-20 min. When appropriately warm, mice were restrained individually. The tail was swabbed with gauze dampened in 70% ethanol. The needle of a BD microfine syringe (20-25G) with LNP solution was carefully inserted into one of the side tail veins and applying slow pressure to the plunger a maximum volume of 100μL (for mice of 20-25g) was injected. The needle was removed from the vein and the local bleeding stopped by applying slight pressure to the puncture site with dry gauze. Animals were subsequently observed for at least 10 minutes in their cage. Each injection was equivalent to 5 pg Flue mRNA and each mouse was injected 3 times in one week intervals using the batch of LNP formulation. LNP formulations were kept at 4°C and monitored for their physico-chemical characteristics prior to their usage (Table 6). 24h post injection, blood samples were taken and hEPO protein content was determined using a commercially available hEPO-ELISA kit according to the manufacturers protocol. mRNA synthesis
Human erythropoietin (hEPO) mRNA was produced from a linearized peTheRNA vector using eTheRNA-optimized in vitro transcription (IVT) reaction conditions and purified via cellulose. Uridine was fully substituted by N1-Methylpseudouridine (N1ψ) to generate N1Ψ-modified mRNA. LNP production Lipid based nanoparticles are produced by microfluidic mixing of an mRNA solution in sodium acetate buffer (100mM, pH4) and lipid solution in a 3:1 volume ratio at a speed of 12mL/min using the NanoAssemblr Benchtop (Precision Nanosystems). The lipid solution contained a mixture of the ionizable lipid of interest, DSPC (Avanti), Cholesterol (Sigma) and DMG-PEG2000 (Avanti). LNPs were dialyzed against TBS (10000 times more TBS volume than LNP volume) using slide- a-lyzer dialysis cassettes (20K MWCO, 3mL, ThermoFisher). Size, polydispersity and zeta potential were measured with a Zetasizer Nano (Malvern). mRNA encapsulation was measured by standard Ribogreen RNA assay (Invitrogen). LNPs were produced at a standard molar ratio ionizable lipid/DSPC/cholesterol/DMG-PEG2000 of about 50/10/38.5/1.5. Fluc mRNA was encapsulated in all LNPs as reporter mRNA, at a mRNA/ionizable lipid molar ratio of 1/6. A list of relevant physico-chemical properties for the LNP composition based on IL14 at different timepoints is shown below in Table 4. Table 4. Physico-chemical characteristics of LNPs Timepoints Composition Ratio [mol %] Size [nm] PDI EE% T0 7951 0102 94
Figure imgf000106_0001
g g j p as mIU/mL. As shown, expression of hEPO may not affected by repeated administration of an LNP containing an ionizable lipid according to the invention.

Claims

CLAIMS 1. An ionizable lipid represented by formula (I)
Figure imgf000107_0001
wherein 5 n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. 2. An ionizable lipid as defined in claim 1 and represented by formula (I)
Figure imgf000109_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH. 3. An ionizable lipid as defined in any one of claims 1 to 2 and represented by formula (I)
Figure imgf000111_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1,
2,
3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH.
4. An ionizable lipid as defined in any one of claims 1 to 3 and represented by formula (I)
Figure imgf000113_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl.
5. An ionizable lipid as defined in any one of claims 1 to 4 and represented by formula (I)
Figure imgf000114_0001
wherein n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, 3, and 4; wherein the sum of n and m is at least 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene- and -C2-6alkynylene-; wherein each of said -C1-6alkylene-, -C2-6alkenylene- and -C2- 6alkynylene- optionally and independently comprises one or more heteroatoms selected from N, O and S and/or is optionally and independently substituted with from 1 to 3 -OH substituents; each instance of FG is independently selected from -O-, -NRa-, -C(O)-, -OC(O)-, -C(O)O-, - OC(O)O-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O-, -OC(O)NRa-, -NRaC(S)O-, -NRaC(O)S-, - OC(S)NRa-, -SC(O)NRa-, and -NRaC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, and -C1-12alkylene-; each instance of R3 is independently selected from -halo, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, - OH, -O-C1-6alkyl, -C(O)H, and -OC(O)-C1-6alkyl; wherein each of said -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, -O-C1-6alkyl, -SH, -OC(O)-C1-6alkyl, -NR4R4’, Cy1, -C(O)- C1-6alkylene-NR4R4’, -C(O)-C1-6alkylene-Cy1, -C(O)O-C1-6alkylene-NR4R4’, -C(O)O-C1- 6alkylene-Cy1, -OC(O)-C1-6alkylene-NR4R4’, and -OC(O)-C1-6alkylene-Cy1; each instance of R4 and each instance of R4’ is independently selected from -H, -C1-6alkyl, -C(O)- C1-6alkyl, and -C(O)O-C1-6alkyl; wherein each of said -C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents independently selected from Het1, and Ar1; or each instance of R4 and R4’ taken together with the N atom to which they are attached forms a 5-10 membered aromatic or non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional heteroatoms selected from O, N and S, and/or is optionally substituted with from 1 to 3 substituents selected from -C1-6alkyl, and - C1-6alkyl-OH; each instance of Cy1 is independently a 5- to 10-membered aromatic or non-aromatic cycle optionally and independently comprising 1 to 5 heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 5 substituents independently selected from -halo, -C1-6alkyl, -C1-6alkyl-OH, -OH, -NRbRb’, and -C1-6alkyl-NRbRb’; wherein said Cy1 comprises at least 1 N atom; each instance of Het1 is independently a 5- to 10-membered non-aromatic heterocycle comprising at least one N atom, optionally and independently comprising one or more additional heteroatoms selected from O, N and S and/or optionally and independently substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1- 6alkyl-OH; each instance of Ar1 is independently a 5- to 6-membered aromatic cycle optionally and independently comprising one or more heteroatoms selected from O, N and S and/or optionally substituted with from 1 to 3 substituents independently selected from -halo, -C1- 6alkyl, -C3-6cycloalkyl, -OH, -O-C1-6alkyl, -S-C1-6alkyl, and -NRbRb’; and each instance of Rb and each instance of Rb’ is independently selected from -H, -C1-6alkyl, and C1-6alkyl-Ph; or each instance of Rb and Rb’ taken together with the N atom to which they are attached forms a 5- to 10-membered non-aromatic heterocycle; said heterocycle optionally further comprises one or more additional N atoms, and/or is optionally substituted with from 1 to 3 substituents independently selected from -C1-6alkyl, and -C1-6alkyl-OH.
6. An ionizable lipid as defined in any one of claims 1 to 5 and represented by formula (Ia)
Figure imgf000116_0001
wherein m is an integer selected from 3, and 4; each instance of R1 is independently selected from -H, -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; each instance of R2 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -OH, - OC(O)-R7, and -C(O)O-R7; wherein in each instance of R1 and R2, the total number of C atoms of R1 and R2 together with the N atom to which they are attached, is at least 8; each instance of R7 is independently selected from -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O- C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; each instance of Y is independently selected from a direct bond, and -CH2-; each instance of FG is independently selected from -O-, -NRa-, -OC(O)-, -NRaC(O)-, - NRaC(O)O-, and -OC(O)NRa-; each instance of Ra is independently selected from -H, and -C1-6alkyl; each instance of Z is independently selected from a direct bond, -C1-12alkylene-, -C2- 12alkenylene-, -C2-12alkynylene-, -C1-12alkylene-C(O)-, -C1-12alkylene-OC(O)-,-(CH2-CH2-O- )x, and -(CH2-CH(CH3)-O-)y ; wherein each of said -C1-12alkylene-, -C2-12alkenylene- and -C2- 12alkynylene- optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents independently selected from -halo, -OH, and -O-C1-6alkyl; wherein each instance of x and each instance of y is an integer independently selected from 1 to 10; each instance of R3 is independently selected from -CH3, -OH, -CH2-OH, -CH2-SH, -CH2-NR4R4’, and -C(O)H; and each instance of R4 and each instance of R4’ is independently selected from -H, and -C1-6alkyl.
7. An ionizable lipid as defined in any one of claims 1 to 6 and represented by formula (IIa), or formula (IIb)
Figure imgf000117_0001
wherein each instance of X1, each instance of X2, and each instance of X3 is independently selected from a direct bond, -C1-6alkylene-, -C2-6alkenylene-, and -C2-6alkynylene-; each instance of R5 and each instance of R5’ is independently selected from -C1-20alkyl, -C2- 5 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X1, X2, X3, R5 and R5’, the total number of C atoms of in X1, X2, X3, R5 and R5’ together with the N atom to which they are attached, is at least 5; and wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined in any one of claims 1 to 6.
8. An ionizable lipid as defined in any one of claims 1 to 6 and represented by formula (IIIa), or formula (IIIb)
Figure imgf000118_0001
each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C1-20alkyl, -C2- 20alkenyl and -C2-20alkynyl; wherein each of said -C1-20alkyl, -C2-20alkenyl and -C2-20alkynyl optionally and independently comprises one or more heteroatoms selected from O, N and S and/or is optionally and independently substituted with from 1 to 3 substituents selected from -OH, -O-C1-20alkyl, -O-C2-20alkenyl, -OC(O)-C1-20alkyl, and -OC(O)-C2-20alkenyl; wherein in each instance of in X4, X5, R6 and R6’, the total number of C atoms of in X4, X5, R6 and 5 R6’ together with the N atom to which they are attached, is at least 6; and wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, Rb’, n and m are as defined in any one of claims 1 to 6.
9. An ionizable lipid as defined in any one of claims 1 to 6 and represented by formula (IIIb)
Figure imgf000119_0001
wherein n is 1: m is 3; each instance of X4 and each instance of X5 is independently selected from -C1-12alkylene-; each instance of R6 and each instance of R6’ is independently selected from -C8-20alkyl, -C8- 20alkenyl and -C8-20alkynyl; wherein Y, FG, Z, R3, R4, R4’, Cy1, Het1, Ar1, Ra, Rb, and Rb’ are as defined in any one of claims 1 to 6.
10. An ionizable lipid as defined in claim 1 and being selected from the list comprising:
Figure imgf000119_0002
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
11 . A lipid nanoparticle or lipid nanoparticle composition comprising an ionizable lipid as defined in any one of claims 1 to 10.
12. The lipid nanoparticle or lipid nanoparticle composition according to claim 11 , further comprising a phospholipid, a sterol and/or a PEG lipid.
13. The lipid nanoparticle or lipid nanoparticle composition according to any one of claims 11 to 12, further comprising an active agent, in particular a nucleic acid, preferably mRNA.
14. Use of an ionizable lipid as defined in any one of claims 1 to 10 in the manufacture of a lipid nanoparticle or lipid nanoparticle composition.
15. A pharmaceutical composition comprising a lipid nanoparticle or lipid nanoparticle composition as defined in any one of claims 11 to 13, and a pharmaceutically acceptable agent.
PCT/EP2023/079320 2022-10-21 2023-10-20 Ionizable lipids WO2024084056A1 (en)

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