Ionisable lipids

Abstract

The present disclosure relates to ionisable lipids of Formula I and related structures that comprise a headgroup, core, and hydrophobic substituents. The lipids are capable of forming lipid particles, including lipid nanoparticles (LNPs), in combination with additional lipids such as neutral lipids, charged lipids, structural lipids, or PEGylated lipids. The lipid particles are suitable for delivery of therapeutic agents, including polynucleotides, peptides, antibodies, and small molecules. Compositions comprising the ionisable lipids and methods of forming and using the lipid particles are also provided.

Description

FIELD The present disclosure relates to ionisable lipids that can be used, in combination with other lipid molecules, to form lipid nanoparticles for delivery of therapeutic agents, such as nucleic acids (e.g., oligonucleotides, messenger RNA), small molecules, peptides, antibodies to a subject. BACKGROUND There are many challenges associated with targeted drug delivery of therapeutic agents to affect a desired response in a biological system. For example, nucleic acid-based therapeutics have enormous potential but there remains a need for more effective delivery of nucleic acids to appropriate sites within a cell or organism in order to realize this potential. Therapeutic nucleic acids include, e.g., messenger RNA (mRNA), antisense oligonucleotides, ribozymes, DNAzymes, plasmids, immune stimulating nucleic acids, antagomir, antimir, mimic, supermir, and aptamers. Some nucleic acids, such as mRNA or plasmids, can be used to effect expression of specific cellular products as would be useful in the treatment of, for example, diseases related to a deficiency of a protein or enzyme, or efficient CRISPR-Cas9 delivery as a gene editing instrument. Lipid nanoparticles (LNPs) are formed from four components comprised of an ionisable lipid, helper lipid, cholesterol, and PEG or PEGylated lipids. These are essential for the formation, and stability of the LNP and further allows its compatibility with the cell, allowing to fuse to the effect delivery of its nucleic acid cargo. As mRNA is unstable on its own, lipid nanoparticles are used for its delivery, protecting it against nuclease degradation, decreasing immune response, and enabling cellular uptake in target cells. LNPs have emerged as the most prevalent class of FDA approved nanomedicines offering a safe and effective platform. lonisable lipids play a pivotal role in LNPs by facilitating efficient encapsulation of nucleic acids, promoting cellular entry, and endosomal release. lonisable lipids are amphiphilic molecules having a lipophilic region containing one or more hydrocarbon groups and a hydrophilic region containing at least one positively charged or ionisable polar head group. Such lipids are pH responsive and are positively charged at low pH allowing it to electrostatically complex to the negatively charged mRNA, to facilitate transport across the cell membrane. Once internalised in the cell the positive charge of the ionisable lipid can assist with endosomal escape and release into the cytosol to enable protein expression in the host cell. The effectiveness of the LNP is dependent on different physicochemical characteristics, including their acid dissociation constant (pKa) value and toxicity profile. It is desirable that the molecular shape of the ionisable lipids form an inverted cone morphology that is brought about by variation of the hydrophobe, core and headgroup. For example, multiple hydrophobes, branching of the hydrophobe, or unsaturation of the hydrophobe is more likely to create an inverted cone shaped molecular shape that enables membrane fusion and uptake into the cell interior for endosomal escape and cytosol delivery. It will be apparent to the skilled person that there is an on-going need for improved ionisable lipid compounds which are suitable to form lipid particles, such as LNPs, for delivery of therapeutic agents, such as polynucleotides. SUMMARY The present disclosure provides novel ionisable lipids of Formula I and related structures which, through variations in hydrophobe, core, and headgroup design, may adopt inverted cone geometries that promote membrane fusion and uptake. In particular embodiments of the present invention, these novel ionisable lipids can form lipid particles, for example LNPs, in the presence of additional lipids including one or more of neutral lipids, charged lipids, structural lipids, stabilisers such as PEGylated lipids and analogues thereof, which can be used for the delivery of therapeutic agents, such as polynucleotides, peptides, antibodies, and / or small molecules. Compositions comprising such lipid particles, and methods of forming lipid nanoparticles are also provided. In one aspect there is provided an ionisable lipid of Formula I, or an ionic form thereof: z (I) wherein: Ri is selected from optionally substituted Ci-Cealkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted Ci-Ceheteroalkenyl, optionally substituted Ci-Ceheteroalkynyl, optionally substituted Ci-Cehydroxyalkyl, optionally substituted Ci-Cealkoxyalkyl, optionally substituted Ci-Ceaminoalkyl, or optionally substituted Ci-Cealkylamino; Z is selected from -OR4, -NR4R5, or -SR4; R4 and R5 are independently selected from the group consisting of hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, or Ci-ealkoxyalky; or Ri and Z together with the nitrogen to which they are attached join to form a 4- to 7- membered heterocyclic ring having (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein the additional heteroatoms are independently selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted with one or more substituents and optionally fused with one or more cyclic or heterocyclic rings; Xi, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C7-22alkyl, optionally substituted C7-22alkenyl, optionally substituted C7-22alkynyl, optionally substituted C?-22acyl, or C7-22alkyl or C7-22alkenyl optionally interrupted with at least one of -0-, -S-, -S-S-, -OC(O)-, -C(O)O-, -00(0)0-, -C(0)NH-, or -NHC(O); wherein each of Xi, X2,and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN); each Y is either the same or different and independently selected from -O-, -NR3-, or -S-; and R3 is selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that (a) when Ri and Z together with the nitrogen to which they are attached join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when any of Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of from 2 to 16 methylene units. In embodiments, Ri may be selected from Ci-ealkyl, Ci-ehydroxyalkyl or Ci-ealkoxyalkyl; Z may be selected from -OR4, -NR4R5, or -SR4; R4 and R5 may be independently selected from the group consisting of hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, and Ci-ealkoxyalkyl; Xi, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C?-22alkenyl, optionally substituted C?-22alkynyl, optionally substituted C?-22acyl, or C?-22alkyl or C?-22alkenyl optionally interrupted with at least one of-0-, -S-, -S-S-, -OC(O)-, -0(0)0-, -00(0)0-, C(0)NH-, or -NHC(O); wherein each of Xi, X2, and X3 may terminate with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN); each Y is either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 is selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that when Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of from 2 to 16 methylene units. In other embodiments, Ri and Z together with the nitrogen to which they are attached may join to form a 4- to 7- membered heterocyclic ring having (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein the additional heteroatoms are independently selected from nitrogen and oxygen, wherein the heterocyclic ring may be optionally substituted with one or more substituents and optionally fused with one or more cyclic or heterocyclic rings; Xi, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C7-22alkenyl, optionally substituted C?-22alkynyl, optionally substituted C?-22acyl, or C7-22alkyl or C7-22alkenyl optionally interrupted with at least one of -0-, -S-, -S-S-, -OC(O)-, -C(O)O-, -00(0)0-, -00(0)0-, -C(0)NH-, or -NHC(0); wherein each of Xi, X2, and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-0H); or a cyano (-CN); each Y is either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 is selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that (a) when Ri and Z together with the nitrogen to which they are attached join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of from 2 to 16 methylene units. In embodiments, Ri and Z together with the nitrogen to which they are attached may join to form a heterocyclic ring selected from an optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrroline, optionally substituted pyrazolidinyl, optionally substituted imidazolidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted azepinyl, optionally substituted diazepanyl, optionally substituted indolyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl. In another aspect there is provided a lipid nanoparticle (LNP) comprising an ionisable lipid of any one or more aspects, embodiments or examples described herein. In embodiments, the LNP may further comprise a therapeutic agent, wherein the therapeutic agent may be encapsulated within the LNP. In another aspect there is provided a LNP conjugate comprising an ionisable lipid of any one or more aspects, embodiments or examples described herein, wherein the compounds are chemically attached or hydrogen bonded to a mRNA, small molecule, peptide or antibody. In another aspect there is provided a pharmaceutical composition comprising a plurality of lipid nanoparticles of any one or more embodiments described herein, and a pharmaceutically acceptable carrier. In another aspect there is provided a method of delivering a therapeutic agent to a mammalian cell, including administering the lipid nanoparticle of any one or more embodiments described herein, or the pharmaceutical composition as described herein, to a subject to thereby contact the cell with the lipid nanoparticle or pharmaceutical composition and deliver the therapeutic agent to the cell. In another aspect there is provided a method of treating a disease, disorder or condition in a subject in need of such treatment, comprising administering a lipid nanoparticle of any one or more embodiments described herein, or the pharmaceutical composition as described herein, to the subject to thereby treat the disease, disorder or condition. In some embodiments, the disease, disorder or condition may be selected from the group consisting of a rare disease, an infectious disease, cancer, a proliferative disease, a genetic disease, an autoimmune disease, diabetes, a neurodegenerative disease, a cardiovascular disease, a reno-vascular disease and a metabolic disease. BRIEF DESCRIPTION OF THE DRAWINGS Preferred embodiments of the present disclosure will be further described and illustrated, by way of example only, with reference to the accompanying drawings in which: Figure 1 represents (a) encapsulation efficiency (EE) and (b) particle size and PDI for LNPs prepared using ionisable lipid LI to L7 along with Cholesterol, DOPE and PEG-DMG and mRNA. Figure 2 shows a) partial phase diagram on the effect of pH on the lipid selfassembly of the LNPs prepared using ionisable lipids LI to L5 along with Cholesterol, DOPE and PEG-DMG. The partial phase diagrams were obtained by SAXS at 25C. The boxed region represents the change in self-assembled mesophase structure as pH change. b) one-dimensional SAXS profile for LNP prepared using ionisable lipid (LI to L5), along with Cholesterol, DSPC and PEG-DMG. Figure 3 shows GFP cell expression data on HEK293 cells for in-house prepared control formulated using ionisable lipid SM-102 and for LNPs prepared using ionisable lipid LI to L5 along with Cholesterol, DOPE and PEG-DMG and mRNA. DETAILED DESCRIPTION The present disclosure describes the following various non-limiting examples, which relate to investigations undertaken to identify alternative and improved ionisable lipids for the delivery of therapeutic agents. The novel lipids present biodegradable groups which may assist in reducing toxicity or improving clearance, in vivo. Definitions General Definitions and Terms In the following description, reference is made to the accompanying drawings which form a part hereof, and which is shown, by way of illustration, several embodiments. It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present disclosure. With regards to the definitions provided herein, unless stated otherwise, or implicit from context, the defined terms and phrases include the provided meanings. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired by a person skilled in the relevant art. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Furthermore, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications discussed and / or referenced herein are incorporated herein in their entirety. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present disclosure. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application. Throughout this disclosure, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. For example, reference to “a” includes a single as well as two or more; reference to “an” includes a single as well as two or more; reference to “the” includes a single as well as two or more and so forth. Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the examples, steps, features, methods, compositions, coatings, processes, and coated substrates, referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning. Unless otherwise indicated, the terms “first,” “second,” etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and / or a higher-numbered item (e.g., a “third” item). As used herein, the phrase “at least one of’, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination. It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Throughout the present specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Any embodiment of the present disclosure herein shall be taken to apply mutatis mutandis to any other embodiment of the disclosure unless specifically stated otherwise. Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for embodiments, in organic synthetic chemistry, cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry). Unless otherwise indicated, any recombinant protein, cell culture, and immunological techniques utilized in the present disclosure are standard procedures, well known to those skilled in the art. As used herein the term "derived from" shall be taken to indicate that a specified integer may be obtained from a particular source albeit not necessarily directly from that source. Specific Definitions and Terms As used herein, the terms “lipid particle”, “lipid nanoparticle” or “LNP” shall be understood to refer to lipid-based particles having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) and which comprises a compound of any formulae described herein. In embodiments, LNPs are formulated in a composition for delivery of a polynucleotide to a desired target such as a cell, tissue, organ, tumor, and the like. The LNPs generally comprise an ionisable cationic compound of the present disclosure and one or more of a neutral lipid, charged lipid, sterol and PEGylated lipid. In embodiments, the lipid particle or LNP may be selected from liposomes, cubosomes, hexasomes, or vesicles, where an aqueous volume is encapsulated by amphipathic lipid bilayers (e.g., single; unilamellar or multiple; multilamellar), micelle-like lipid nanoparticles having a non-aqueous core and solid lipid nanoparticles. A "cationic compound", "ionisable cationic compound", "cationic lipid compound", "ionisable cationic lipid compound", “ionisable lipid”, or like terms, refer to a lipid compound of any structural formulae described herein which includes one or more nitrogen-containing groups that are ionisable, i.e., capable of being reversibly protonated and deprotonated depending on pH. lonisable lipids of the invention therefore can exist in a positively charged or neutral form depending on environmental pH. This definition expressly excludes compounds that are permanently cationic, such as quaternary ammonium salts, quaternary heteroaryl salts, and imidazolium salts, which are incapable of reversible ionisation. As used herein, the term “core” refers to the central scaffold of the ionisable lipids of the present disclosure, which comprises a benzyl group to which the hydrophobic substituents (YXi, YX2, YX3) are attached. This core remains structurally consistent across the disclosed series of compounds, thereby providing a fixed framework for variation of the headgroup (Ri-N-Z) and hydrophobic substituents (Xi, X2, and X3). The term "helper lipid" refers to any of a number of lipid species that exist either in an uncharged or neutral zwitterionic form at a selected pH. At physiological pH, such lipids include, but are not limited to, phosphotidylcholines such as 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and phophatidylethanolamines such as 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelins (SM). Neutral lipids may be synthetic or naturally derived. Neutral lipids include those lipids sometimes referred to as ‘non-cationic’ lipids. The term "charged lipid" refers to any of a number of lipid species that exist in either a positively charged or negatively charged form independent of the pH within a useful physiological range e.g. pH ~3 to pH ~9. Non-limiting examples of charged lipids include phosphatidylserines, phosphatidic acids, phosphatidylglycerols, phosphatidylinositols, sterol hemisuccinates, dialkyl trimethylammonium-propanes, (including DOTAP and DOTMA), dialkyl dimethylaminopropanes, ethyl phosphocholines, and dimethylaminoethane carbamoyl sterols. The term "polynucleotide" as used herein refers to a polymer containing at least two deoxyribonucleotides or ribonucleotides in either single- or double-stranded form and includes DNA, RNA, and hybrids thereof. DNA may be in the form of antisense molecules, plasmid DNA, cDNA, PCR products, or vectors. RNA may be in the form of small hairpin RNA (shRNA), messenger RNA (mRNA), single guide RNA (sgRNA), self-amplifying RNA (saRNA), antisense RNA, miRNA, micRNA, multivalent RNA, dicer substrate RNA or viral RNA (vRNA), and combinations thereof. Polynucleotides include those containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, and which have similar binding properties as the reference polynucleotide. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2'-O-methyl ribonucleotides, and peptide-nucleic acids (PNAs). Unless specifically limited, the term encompasses polynucleotides containing known analogues of natural nucleotides that have similar binding properties as the reference polynucleotide. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res., 19:5081 (1991); Ohtsuka et al., J. Biol. Chern., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91-98 (1994)). An "effective amount" or "therapeutically effective amount" of an active agent or therapeutic agent such as a therapeutic nucleic acid is an amount sufficient to produce the desired effect, such as an increase or inhibition of expression of a target sequence in comparison to the normal expression level detected in the absence of the nucleic acid. Suitable assays for measuring expression of a target gene or target sequence include, examination of protein or RNA levels using techniques known to those of skill in the art such as dot blots, northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, fluorescence or luminescence of suitable reporter proteins, as well as phenotypic assays. "Pharmaceutically acceptable carrier, diluent or excipient", or like terms, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending, complexing, or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxy toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E (alpha-tocopherol), vitamin C, xylitol, and other species disclosed herein. "Pharmaceutically acceptable salt" includes both acid and base addition salts. Lists of suitable salts may be found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). As used herein, "encapsulation efficiency" refers to the amount of a nucleic acid that becomes part of an LNP composition, relative to the initial total amount of polynucleotide used in the preparation of the LNP composition. For example, if 95 mg of nucleic acid are encapsulated in an LNP composition out of a total 100 mg of nucleic acid initially provided to the composition, the encapsulation efficiency may be given as 95%. As used herein, "encapsulation" may refer to complete, substantial, or partial incorporation, loading or entrapment. As used herein, the term "subject" shall be taken to mean any animal, such as a mammal, and including humans. Exemplary subjects include but are not limited to humans and non-human primates. For example, the subject is a human. As used herein, the term "mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. Chemical Definitions and Terms The term "alkyl" includes straight-chained, branched, and cyclic alkyl groups and includes both unsubstituted and substituted alkyl groups. Accordingly, the expression “optionally substituted alkyl” as used herein encompasses straight-chained, branched, and cyclic alkyl groups, either unsubstituted or substituted with one or more substituents as described herein. Unless otherwise indicated, the alkyl groups typically contain from 1 to 22 carbon atoms. The alkyl groups may for example contain carbon atoms from 1 to 22, 1 to 20, 1 to 11, or 1 to 6. The alkyl groups may for example contain carbon atoms from 2 to 22, 2 to 20, 2 to 11, or 2 to 6. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl. n-butyl, n-pentyl, isobutyl, t-butyl, isopropyl, n-octyl, n-heptyl, ethylhexyl, cyclopentyl, cyclohexyl, cyclo heptyl, adamantyl, norbornyl, decanyl, pentadecanyl, dimethyloctane, and the like. Unless otherwise noted, alkyl groups may be mono- or polyvalent. As used herein, a “straight-chained alkyl” or “straight chain alkyl” refers to an unbranched alkyl group having no interrupting groups and no tertiary carbon atoms bearing substituents. As used herein, the term "alkenyl" encompasses both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Further examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, but-2-enyl, decenyl, pentadecenyl, and the like. As used herein, the term "alkynyl" encompasses both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Further examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, decynyl, pentadecynyl, and the like. The term "heteroalkyl" includes both straight-chained, branched, and cyclic alkyl groups interrupted with one or more heteroatoms (e.g. 1-3) independently selected from S, O, and N. It will be appreciated that the term "heteroalkyl", may also include straight-chained, branched, and cyclic alkyl groups interrupted with one or more heteroatoms (e.g. 1-3) independently selected from S, O, and N wherein the alkyl chain may also terminate with a heteroatom comprising group selected from SH, OH or NH2, for example an alkanolamine. The heteroalkyl may be unsubstituted or substituted. Unless otherwise indicated, the heteroalkyl groups may contain from 1 to 22 carbon atoms. The heteroalkyl groups may for example contain carbon atoms from 1 to 22, 1 to 20, or 1 to 11. The heteroalkyl groups may for example contain carbon atoms from 2 to 22, 2 to 20, or 2 to 11. Examples of "heteroalkyl" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, decoxy, pentadecoxy, -CH2OCH3, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2SCH3, and the like. Unless otherwise noted, heteroalkyl groups may be mono-, di- or polyvalent. The term "heteroalkenyl” includes both straight-chained, branched, and cyclic alkenyl groups as described herein with one or more heteroatoms (e.g. 1-3) independently selected from S, O, and N with both unsubstituted and substituted alkenyl groups. Unless otherwise indicated, the heteroalkenyl groups may contain from 1 to 22 carbon atoms. The heteroalkenyl groups may for example contain carbon atoms from 1 to 22, 1 to 20, or 1 to 11. Unless otherwise noted, heteroalkenyl groups may be mono- or polyvalent. The term "heteroalkynyl” includes both straight-chained, branched, and cyclic alkynyl groups as described herein with one or more heteroatoms (e.g. 1-3) independently selected from S, O, and N with both unsubstituted and substituted alkenyl groups. Unless otherwise indicated, the heteroalkynyl groups may contain from 1 to 22 carbon atoms. The heteroalkynyl groups may for example contain carbon atoms from 1 to 22, 1 to 20, or 1 to 11. Unless otherwise noted, heteroalkynyl groups may be mono- or polyvalent. As used herein, the terms “carbocyclic” and “carbocyclyl” represent a cyclic group in which the ring atoms are all carbon atoms, for example from 3 to 20 ring atoms. A carbocyclyl group may be saturated, unsaturated, aromatic, or non-aromatic. The terms encompass single-ring systems such as cyclopentyl, cyclohexyl, phenyl, or cyclohexenyl, as well as fused-ring systems such as naphthyl and fluorenyl. As used herein, the term “cycloalkyl” represents a saturated carbocyclic group, e.g. from 3 to 20 carbon ring atoms, which may be monocyclic or polycyclic. A bicyclic group may be fused or bridged such as a bridged cyclic hydrocarbon, e.g. optionally substituted cyclohexane ring with a methylene bridge such as optionally substituted norbomene. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As will be understood, an “aromatic” group means a cyclic group having 4m+2 7t electrons, where m is an integer equal to or greater than 1. As used herein, “aromatic” is used interchangeably with “aryl.” Aromatic groups may contain 6-18 ring atoms and can be monocyclic (e.g. phenyl, pyridyl) or polycyclic (e.g. naphthyl, phenanthryl, anthracyl). Aromatic groups may contain one to three heteroatoms such as nitrogen, oxygen, or sulfur. Examples include phenyl, naphthyl, biphenyl, phenanthryl, anthracyl, pyridyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, indolyl, and benzofuranyl. Aromatic groups may be mono- or polyvalent. As used herein, the terms “aromatic carbocycle” or “aromatic carbocyclyl” represent an aromatic carbocyclic group in which all ring atoms are carbon, for example phenyl, naphthyl, or fluorenyl. As used herein, the terms “heterocyclic” and “heterocyclyl” represent a cyclic group containing from 4 to 7 ring atoms, in which one to three of the ring carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur. Heterocyclyl groups may be monocyclic (e.g. pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, diazepanyl) or bicyclic (e.g. triazabicyclodecenyl). As used herein, the terms “aromatic heterocycle”, “aromatic heterocyclyl”, and “heteroaryl” represent an aromatic cyclic group containing from 3 to 20 ring atoms, in which one to three of the ring carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen, or sulfur. Heteroaryl groups may be monocyclic (e.g. pyridyl, pyrimidinyl, furanyl, pyrrolyl, imidazolyl, pyrazyl) or polycyclic (e.g. benzimidazolyl, quinolinyl, indolyl). Polycyclic heteroaryl groups include those in which only one of the fused rings is aromatic. As used herein, the term "cyano" represents a -ON moiety. As used herein, the term “hydroxyl” represents a -OH moiety. As used herein, the term "alkoxy" represents an -O-alkyl group in which the alkyl group is as defined supra. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, and the different butoxy, pentoxy, hexyloxy and higher isomers. As used herein, the term "acyl" represents an -C(O)-alkyl group in which the alkyl group is as defined supra. Examples include formyl, acetyl, propionyl, and the different butyryl, acrylyl and higher isomers. Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g.,alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. The term "optionally fused" means that a group is either fused to another ring system or unfused, and “fused” refers to one or more rings that share at least two common ring atoms with one or more other rings. Fusing may be provided by one or more carbocyclic or heterocyclic rings, as defined herein, or be provided by substituents of rings being joined together to form a further ring system. The fused ring may be a 5, 6 or 7-membered ring of between 5 and 10 ring atoms in size. The fused ring may be fused to one or more other rings, and may for example contain 1 to 4 rings. As used herein, the term “saturated” refers to a group where all available valence bonds of the backbone atoms are attached to other atoms. Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine, and the like. As used herein, the term “unsaturated” refers to a group where at least one valence bond of two adjacent backbone atoms is not attached to other atoms. Representative examples include, but are not limited to, alkenes (e.g., -CH2-CH2CH=CH), phenyl, pyrrole, and the like. As used herein, the term “optionally substituted” refers to a group being unsubstituted or substituted as described herein. The substitution may include, but is not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylhydroxy, alkoxy, alkylamino, alkylester, alkylether, hydroxy alkylether, phosphoryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or heteroaryl. As used herein, the term “substituted” refers to a group having one or more hydrogens or other atoms removed from a carbon or suitable heteroatom and replaced with a further group (i.e., substituent). As used herein, the term “unsubstituted” refers to a group that does not have any further groups attached thereto or substituted therefore. lonisable Lipids lonisable lipids disclosed in the prior art often exhibit limitations such as suboptimal acid dissociation constants (pKa), poor encapsulation efficiency, undesirable toxicity, or inadequate biodegradability. In addition, structural features such as the presence of only a single linear hydrophobic chain, as found in some known cationic lipids, may limit the ability of those molecules to adopt inverted cone geometries that promote endosomal escape. The ionisable lipids of the present disclosure address one or more of these limitations while maintaining a consistent core scaffold. In particular, the core structure remains fixed, while variations in the hydrophobes (YXi, YX2, and YX3) and the ionisable headgroup (Ri-N-Z) provide structural diversity. Multiple hydrophobic substituents, whether linear, branched, unsaturated, or interrupted, allow the compounds to adopt overall inverted cone geometries that favour membrane fusion and intracellular delivery. At the same time, retention of the same central core provides a coherent platform for comparative optimisation of physicochemical and biological properties across the disclosed series. Accordingly, the present disclosure provides novel ionisable lipids of Formula I and related structures (including Formulae IA-ID) which are capable of being formulated with other lipids, for example neutral lipids, charged lipids, PEGylated lipids, and stabilisers, to form lipid nanoparticles (LNPs) suitable for encapsulating therapeutic agents, including polynucleotides, peptides, antibodies, and small molecules. In embodiments, the ionisable lipids of the present disclosure may provide for advantages over other select prior art ionisable cationic lipid compounds including one or more of: mimic cell membrane; improved endocytosis; improved complexation with a therapeutic agent, i.e. nucleotide; beneficial pKa properties; improved encapsulation efficiency as part of an LNP; reduced toxicity; improved biodegradability; and improved LNP formation. It will be understood that in the ionisable lipids of the present disclosure, the headgroup is provided by the Ri-N-Z functionality. This headgroup remains structurally and functionally conserved across the scope of the invention, as it always comprises an ionisable nitrogen atom capable of protonation and deprotonation in a pH-dependent manner. This ionisable character provides the critical functionality for complexation with therapeutic agents, such as polynucleotides, and for pH-triggered membrane fusion. Structural variations may occur, for example, Ri and Z may be present as separate substituents, or together with the nitrogen may form a heterocyclic ring, yet the fundamental architecture and function of the headgroup is preserved. These structural variants all follow the same design principle: they provide an ionisable amine environment that imparts pH-responsiveness, enables therapeutic complexation, and contributes to inverted-cone molecular geometry of the lipid. In one aspect, the present disclosure provides for an ionisable lipid of Formula I, or an ionic form thereof: z (I) wherein: Ri may be selected from optionally substituted Ci-Cealkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted Ci-Ceheteroalkenyl, optionally substituted Ci-Ceheteroalkynyl, optionally substituted Ci-Cehydroxyalkyl, optionally substituted Ci-Cealkoxyalkyl, optionally substituted Ci-Ceaminoalkyl, or optionally substituted Ci-Cealkylamino; Z may be selected from -OR4, -NR4R5, or -SR4; R4 and R5 may each be independently selected from the group consisting of hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, or Ci-ealkoxyalky; or Ri and Z together with the nitrogen to which they are attached may join to form a 4- to 7- membered heterocyclic ring having (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein the additional heteroatoms are independently selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted with one or more substituents and optionally fused with one or more cyclic or heterocyclic rings; Xi, X2, and X3 may each be present, and may be either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C?-22alkenyl, optionally substituted C?-22alkynyl, or optionally substituted C?-22acyl, or C?-22alkyl or C7-22alkenyl optionally interrupted with at least one of -O-, -S-, -S-S-, -OC(O)-, -C(O)O-, -OC(O), -C(0)NH-, or -NHC(O)-; wherein each of Xi, X2, and X3 may terminate with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN); each Y may be either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 may be selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that (a) when Ri and Z together with the nitrogen to which they are attached may join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when any of Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion may consist of from 2 to 16 methylene units. For the avoidance of doubt, when Ri and Z are present as open-chain substituents, they are defined according to the groups set out above. In the alternative embodiment, Ri and Z together with the nitrogen atom to which they are attached form part of a heterocyclic ring. In this latter case, the definitions of open-chain Ri and Z do not limit the structure of the ring; however, both alternatives are encompassed within the same headgroup architecture, namely an ionisable nitrogen moiety capable of reversible protonation and deprotonation. In certain embodiments, when Ri is a heteroalkyl, heteroalkenyl, or heteroalkynyl group, it comprises at least two methylene (-CH2-) units prior to the attachment point to nitrogen, such that the heteroatom is separated from the nitrogen by a methylene spacer (e.g., -CH2CH2-OR4, -CH2CH2-NR4R5). For example, Ri may be selected from Ci-ealkyl, Ci-ehydroxyalkyl, Ci-eheteroalkyl or Ci-ealkoxyalkyl. In some embodiments, Ri may be selected from Ci-ealkyl, Ci-ehydroxyalkyl or Ci-ealkoxyalkyl; Z may be selected from -OR4, -NR4R5, or -SR4; R4 and R5 may each be independently selected from the group consisting of hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, and Ci-ealkoxyalkyl; Xi, X2, and X3 may each be present, and may either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C?-22alkenyl, optionally substituted C?-22alkynyl, optionally substituted C?-22acyl, or C?-22alkyl or C?-22alkenyl optionally interrupted with at least one of-O-, -S-, -S-S-, -OC(O)-, -C(O)O-, -00(0)0-, C(0)NH-, or -NHC(O); wherein each of Xi, X2, and X3 may terminate with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN); each Y is either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 may be selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that when Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion may consist of from 2 to 16 methylene units. In some embodiments, Ri may be selected from Ci-ealkyl, Ci-ehydroxyalkyl, Ci-eheteroalkyl, or Ci-ealkoxyalkyl. In certain embodiments, Ri may be selected from Ci-ealkyl, Ci-ehydroxyalkyl, or Ci-ealkoxyalkyl. In some more specific embodiments, Ri may be selected from -CH3, -(CH2)2OH, or -(CH2)2OCH3. In embodiments, Z may be selected from -OR4, -NR4R5, or -SR4. R4 and R5 may each be independently selected from hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, or Ci-ealkoxyalkyl. In some more specific embodiments, Z may be selected from -OH, -0CH3, -OCH2CH2OH, -NHCH3, -N(CH3)2, or -N(CH2CH3)2. In other embodiments, Ri and Z together with the nitrogen to which they are attached join to form a 4- to 7- membered heterocyclic ring having (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein the additional heteroatoms are independently selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted with one or more substituents and optionally fused with one or more cyclic or heterocyclic rings; Xi, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C?-22alkenyl, optionally substituted C?-22alkynyl, optionally substituted C?-22acyl, or C?-22alkyl or C?-22alkenyl optionally interrupted with at least one of -0-, -S-, -S-S-, -0C(0)-, -0(0)0-, -00(0)0, -C(0)NH-, or -NHC(0); wherein each of Xi, X2, and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-0H); or a cyano (-CN); each Y is either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 is selected from the group consisting of hydrogen and Ci-ealkyl; with the proviso that (a) when Ri and Z together with the nitrogen to which they are attached join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of from 2 to 16 methylene units. In certain embodiments, the heterocyclic or heteroaryl groups encompassed by the definitions of Ri and Z together with the nitrogen to which they are attached do not comprise permanently cationic groups. For example, in some embodiments, the ionisable lipids exclude heterocyclic or heteroaryl rings in which the nitrogen atom is permanently quaternised. Thus, the ionisable lipids may exclude quaternary ammonium salts, quaternary heteroaryl salts, pyridinium, imidazolium, piperidinium, or related permanently cationic structures. In some embodiments, Ri and Z together with the nitrogen to which they are attached form a heterocyclic moiety as represented by Formulae IA to ID: wherein: X may be selected from CR7, N, or O; when X is O then Rs is absent and when X is CR7 or N then Rs may be selected from the group consisting of hydrogen, Ci-ealkyl, Ci-ehydroxyalkyl, Ci-ealkoxy, Ci-ealkoxyalkyl, Ci-ealkyl optionally interrupted by -O- and substituted with a Ci-ehydroxyalkyl, amino, mono- or di(Ci-6)alkylamino, Ci-eaminoalkyl, mono- or di(Ci-6)dialkylaminoalkyl, or heteroaryl, each of which may be unsubstituted or optionally substituted; and R7, when present, may be selected from the group consisting of hydrogen or Ci-ealkyl; Xi, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C?-22alkyl, optionally substituted C?-22alkenyl, optionally substituted C?-22alkynyl, optionally substituted C?-22acyl, or C?-22alkyl or C?-22alkenyl optionally interrupted with at least one of -0-, -S-, -S-S-, -OC(O)-, -0(0)0-, -OC(O)O-, -00(0)0-, -C(0)NH-, or -NHC(0)-; wherein each of Xi, X2, and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkenyl group; an alkynyl group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-0H); or a cyano (-CN); each Y is either the same or different and independently selected from -0-, -NR3-, or -S-; and R3 is hydrogen or Ci-ealkyl; with the proviso that (a) when Ri and Z together with the nitrogen to which they are attached join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when Xi, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of 2 to 16 methylene units. In certain embodiments, the substituents defined by X and Rs exclude groups that comprise a permanently cationic structure. For example, the ionisable lipids may exclude X / Rs substituents in which the nitrogen atom is permanently quaternised. Thus, in some embodiments, the ionisable lipids do not include quaternary ammonium salts, quaternary heteroaryl salts, pyridinium, imidazolium, or related permanently cationic groups. In embodiments, Z1, Z2,Z3, Z4 and Z5 may each be independently selected from CR9 or NR9; R9 is independently selected from hydrogen, Ci-ealkyl, or Ci-ehydroxy alkyl; wherein the heterocyclic ring of Formulae IA to ID may comprise (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein said additional heteroatoms are independently selected from nitrogen or oxygen; and optionally, for Formulae IC, any two of Z1, Z2, Z3, Z4 and R5 together form a fused 9- or 10-membered non-aromatic bicyclic ring. In certain embodiments, compounds of Formula IC preferably form a heterocyclic ring in the same manner as described generally herein, that is, a nonaromatic 5- to 7-membered heterocyclic ring containing the nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from nitrogen or oxygen. In further embodiments, a subset of Formula IC compounds may alternatively form a fused 9- or 10-membered non-aromatic bicyclic ring, wherein the bicyclic system contains the nitrogen atom and may contain up to two additional heteroatoms independently selected from nitrogen or oxygen. In some embodiments, compounds of Formula IB are such that Z2 and Z3 are each independently selected from CR9 or NR9; however, in certain preferred embodiments Z2 and Z3 are not linked by a double bond. Thus, in these embodiments the heterocyclic ring of Formula IB does not include a C=C unsaturation between the Z2 and Z3 positions. In some embodiments, Z1, Z2, Z3, Z4, and Z5 may each be independently selected from CR9; R9 may be independently selected from H, Ci.4alkyl, or Ci-4hydroxyalkyl; X may be selected from CR7, N, or O; when X is O then Rs may be absent and when X is CR7 or N then Rs may be selected from the group consisting of H, Ci-4alkyl, -(CH2)n-cyl, -(CH2)n-Ar, -(CH2)n-N(R)(R'), -N(R)(R ), -(CH2)n-OR, -(CH2)n-OC(O)R, -(CH2)n-O-(CH2)n-OR, -OR, -HetAr, -(CH2)n-O-(CH2)n-P(O)(OR)(OR'); n is 0, 1, or 2; cyl is an optionally substituted 5- or 6-membered heterocyclyl containing at least one N and optionally one or more additional heteroatoms independently selected from a nitrogen atom and an oxygen atom; R and R' are each independently selected from H or Ci.4alkyl; Ar is an aryl group; and HetAr is a 5- or 6-membered heteroaryl containing at least one N and optionally one or more additional heteroatoms independently selected from a nitrogen atom and an oxygen atom; and R7, when present, may be selected from the group consisting of hydrogen or Ci-ealkyl. In an embodiment, the ionisable lipids of Formulae IA to ID preferably form non-aromatic heterocyclic rings having zero, one, or two additional heteroatoms, wherein the additional heteroatoms are independently selected from nitrogen or oxygen, as described herein. In embodiments, Ri and Z together with the nitrogen to which they are attached may join to form a heterocyclic ring selected from an optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrroline, optionally substituted pyrazolidinyl, optionally substituted imidazolidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted azepinyl, optionally substituted diazepanyl, optionally substituted indolyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl. For example, Ri and Z together with the nitrogen to which they are attached may form a 4- to 7membered heterocyclic ring having (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein said additional heteroatoms are independently selected from nitrogen or oxygen. Such rings may be unsubstituted, optionally substituted with one or more substituents, and / or optionally fused with one or more cyclic or heterocyclic rings. Examples of such heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, pyrroline, pyrazolidinyl, imidazolidinyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepanyl, indolyl, quinolinyl, or isoquinolinyl, each of which may be optionally substituted. Preferably, azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl. In an embodiment, the azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl may be substituted with one or more substituents selected from hydrogen, Ci-Cealkyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy, Ci-Ce alkoxyalkyl, Ci-Cealkyl optionally interrupted by one or more -O- groups and optionally substituted with hydroxy, amino, mono- or di(Ci-C6)alkylamino, Ci-Ceaminoalkyl, mono- or di(Ci-C6)alkylaminoalkyl, and optionally substituted heteroaryl. For example, the azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl may be substituted with one or more substituents selected from hydrogen, methyl, hydroxymethyl, 2-hydroxyethyl, methoxy, 2-(2-hydroxyethoxyjethyl, methylamino, dimethylamino, 2-(dimethylamino)ethyl, and pyridinyl. In preferred embodiments, the azetidinyl, pyrrolidinyl, morpholinyl, or piperazinyl may be substituted with substituents selected from the group consisting of Formulae al-A to al-J, wherein: heterocycle: denotes the attachment point to the Formula al-A; Formula al-B;            Formula al-C; Formula al-D; Formula al-E;            Formula al-F; 4nh Formula al-G; F ormul a a 1 -H;              Formul a a 1 -I; v / / N— Formula al-J. In some embodiments, all three of Xi, X2, and X3 are the same. In other embodiments, Xi, X2, and X3 are different. Combinations where two of Xi, X2, and X3 5 are the same and the third is different are also contemplated. With respect to chain length, in certain embodiments, any uninterrupted methylene (-CH2-) portion within Xi, X2, or X3 consists of from 2 to 16 methylene units. Thus, purely linear saturated alkyl chains having 17 or more methylene units are excluded. However, C7-22 substituents that include interruptions, branching, or 10 unsaturation remain within scope. Accordingly, the uninterrupted methylene (-CH2-) portion within each Xi, X2, or X3 may consist of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 methylene groups. In some embodiments, the uninterrupted methylene (-CH2-) portion consists of from 4 to 10 methylene groups. In some embodiments, Y is -O- and each of Xi, X2, and X3 are independently 15 selected from optionally substituted C7-20 alkyl, optionally substituted C7-11 alkyl, optionally substituted Cs-io alkyl, or C7-22 alkyl or alkenyl optionally interrupted with one or more groups selected from -O-, -S-, -S-S-, -OC(O)-, -0(0)0-, -00(0)0-, -C(0)NH-, or -NHC(O)-. Each of Xi, X2, and X3 terminates with a group selected from a primary, secondary or tertiary alkyl group, an alkenyl group, an alkynyl group, an aromatic ring, a cycloalkyl group having 6 to 9 carbon atoms, hydroxyl (-0H), or cyano (-CN). In further embodiment, Xi, X2, and X3 may either be the same or different and independently selected from a compound of Formula a2: wherein:       denotes the attachment point to Y; Mi and M2 may be absent or present, and when present may be selected from the group consisting of, -0-, -S-, -S-S-, -0C(0)-, -0(0)0-, -00(0)0-, -C(0)NH-, and -NHC(0)-; D and F are each independently an optionally substituted linear or branched Ci-iealkyl; E may be absent or present, and when present represents                    s where denotes attachment points to Y, Mi or M2 at one end and F at the other end; G is selected from the group consisting of hydroxy (-0H), cyano (-C=N), Ci-ealkyl, C3-ucycloalkyl, C2-6alkenyl, C2-6alkynyl, bicyclic hydrocarbon groups, aryl, or heteroaryl; and r and s are each independently an integer from 0 to 10. In some embodiments, Y may be -0- and each of Xi, X2, and X3 are either the same or different and independently selected from a compound of Formula a2: wherein:       denotes the attachment point to Y; Mi and M2 may be absent or present, and when present may be selected from the group consisting of -0-, -0C(0)-, -0(0)0-, -0C(0)0-; D and F may each be independently an optionally substituted linear or branched Ci-iealkyl; E and s are absent; G may be selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, methoxy, C2-6 alkenyl, C2-6 alkynyl, cyclohexyl, substituted or unsubstituted norbomenyl, aryl, heteroaryl or -C=N; and r may be an integer from 2 to 8. In an embodiment, Xi, X2, and X3 may either be the same or different and independently selected from an optionally substituted C7-nalkyl, preferably an 5 optionally substituted C7-ioalkyl, more preferably an optionally substituted Cs-ioalkyl, or Cs-2oalkyl or Cs-2oalkenyl optionally interrupted with at least one of -0-, -S-, -S-S-, -0C(0)-, -0(0)0-, -C(0)NH-, or -NHC(O). In an embodiment, the optionally substituted C7-2oalkyl, or optionally substituted C7-1 xalkyl, or optionally substituted Cs-walkyl is a linear or branched alkyl chain (e.g. a C6 or C8 alkyl of which at least 1 or 2 10 carbons are secondary carbons with methyl, ethyl, hexyl, ethyl acetate or carboxylic acid branches). In an embodiment, when present, Xi, X2, and X3 may either be the same or different and independently selected from the groups consisting of: Formula a2-l; Formula a2-3; Formula a2-2; Formula a2-4; Formula a2-5; Formula a2-6; Formula a2-7; Formula a2-8; Formula a2-9; OH Formula a2-10; Formula a2-ll; Formula a2-12; Formula a2-13; Formula a2-15; Formula a2-14; Formula a2-16; Formula a2-17; 0 Formula a2-18; Formula a2-20; Formula a2-24; Formula a2-25; Formula a2-26; 0 Formula a2-27; O Formula a2-28; O Formula a2-29; 0 Formula a2-32; Formula a2-33; Formula a2-34; Formula a2-36; Formula a2-38; Formula a2-39; 0 i Formula a2-40; Formula a2-41; O Formula a2-42; 0 0 Formula a2-43; Formula a2-44; 0 Formula a2-45; Formula a2-46; Formula a2-47; Formula a2-48; Formula a2-49; wherein:       denotes the attachment point to Y. In a more preferred embodiment, Xi, X2, and X3 may either be the same or different and independently selected from the groups consisting of: Formula a2-l; Formula a2-2; Formula a2-3; TC / ys / y Formula a2-6; 0 Formula a2-20; 0 Formul a a2 -21;                  F ormul a a2-22; 0 Formula a2-24; O Formula a2-7; Formula a2-23; Formula a2-25; Formula a2-26; 0 Formula a2-27; O Formula a2-28; O Formula a2-29; Formula a2-31; Formula a2-32; Formula a2-33; Formula a2-34; Formula a2-36; Formula a2-38; Formula a2-40; Formula a2-41; O Formula a2-42; Formula a2-44; Formula a2-49; wherein:       denotes the attachment point to Y. In some embodiments, the ionisable lipids of Formula I and Formulae IA to ID include substituents Xi, X2, and X3 as independently selected from the groups described with reference to Formula a2. Accordingly, any of the heterocyclic structures defined in Formula I and Formulae IA to ID may be combined with Xi, X2, and X3 5 groups as defined in Formula a2, including the specific examples set out in Formula I and Formulae a2-l to a2-49. In further embodiments, the heterocyclic systems represented by Formulae IA to ID may include substituents wherein one or more of Xi, X2, and X3 are identical, or two are the same and the third is different, and may be optionally interrupted by heteroatoms or functional groups as defined herein. In some 5 embodiments, the ionisable lipids of Formula I and Formulae IA to ID having Xi, X2, and X3 as defined in Formula a2 may further be provided in the form of salts, solvates, stereoisomers, tautomers, or ionic species. In embodiments, the ionisable lipids of Formula I may be selected from the group consisting of: Lipid 33 In embodiments, the ionisable lipid of Formula I, Formula IA, Formula IB, Formula IC, or Formula ID may be selected from the group consisting of: ch3 Lipid 57 Lipid 66 Lipid 84 In some embodiments, the ionisable lipids of Formula I, Formula IA, Formula IB, Formula IC, and Formula ID may have a pKa value in the range of from about 4.5 to about 8. The ionisable lipids of Formula I, Formula IA, Formula IB, Formula IC, and 5 Formula ID may have a pKa value less than about 7, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1 Without wishing to be bound by theory, it is believed that pKa values in a range between 4.5 to 8, for example, in a range between 5 to 7, are particularly beneficial in polynucleotide LNP formulation and efficient delivery. It will be appreciated that each lipid, when dispersed in water, may have a pKa (pKaw), and when formulated as an LNP an apparent pKa (pKaa). The values for pKaw and pKaa can be very different due to the presence of other components in the system, such as helper lipid and PEG-lipids. Lipid Nanoparticles The present disclosure provides for a LNP for delivery of a therapeutic agent, such as a nucleic acid (e.g. RNA), wherein the LNP comprises any one or more of the ionisable lipids of the present disclosure. In embodiments, the LNPs have a mean diameter of from about 30 nm to less than about 250 nm. The particle size of the LNPs comprising a compound of the present disclosure may have a diameter (mean particle diameter) from about 35 nm to about 200 nm. In some embodiments, the LNPs comprising a compound of the present disclosure may have a diameter of less than about 250 nm, 200 nm, 150 nm, 100 nm, or 50 nm. In one embodiment, the lipid particle has a diameter from about 120 to about 160 nm. In one embodiment, the LNPs comprising a compound of the present disclosure may have a diameter from about 15 to about 50 nm. The particle size of the LNPs comprising a compound of the present disclosure can be determined by any means known to the skilled person, such as dynamic light scattering (DLS), cryogenic-transmission electron microscopy (cryo-TEM), scanning electron microscopy (SEM), etc. Typically, LNPs include a range of nanoparticles of a poly dispersity index (PDI) of preferably 0.10- 0.44. The PDI may be used to indicate the homogeneity of a LNP, e.g., the particle size distribution of the lipid nanoparticles. A small (e.g., less than 0.3) poly dispersity index generally indicates a narrow particle size distribution. The LNPs comprising a compound of the present disclosure may have a PDI from about 0.01 to about 0.4, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.4. In some embodiments, the PDI of LNPs comprising a compound of the present disclosure may be from about 0.10 to about 0.25. The PDI of the LNPs comprising a compound of the present disclosure can be determined by any means known to the skilled person, such as dynamic light scattering (DLS). The LNP may comprise more than one ionisable lipid of Formula I, Formula IA, Formula IB, Formula IC, and Formula ID as appropriate. The inclusion of more than one such ionisable lipid may, for example, be employed to achieve a desired selfassembled nanostructure and apparent pKa profile. The LNP may comprise an ionisable lipid of Formula I, Formula IA, Formula IB, Formula IC, and Formula ID and an additional cationic and / or ionisable lipid, for example a cationic and / or ionisable lipid comprising a cyclic or non-cyclic amine. Such additional cationic and / or ionisable lipids may be selected from the non-limiting group consisting of: N-[l-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 2,3-dioleyloxy-N-[2-(sperminecarboxamido)ethyl]-N,N-dimethyl-l-propanaminium trifluoroacetate (DOSPA), N-[l-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP), [(4-hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315), heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6- (undecyloxy)hexyl)amino) octanoate (Lipid H), 8-[(2-hydroxyethyl)[8-(nonyloxy)-8-oxooctyl]amino]-octanoic acid, 1-octylnonyl ester (Modema Lipid 5), (((3,6-dioxopiperazine-2,5-diyl)bis(butane-4, l-diyl))bis(azanetriyl))tetrakis(ethane-2,1-diyl) (9Z,9'Z,9"Z,9"'Z,12Z,12'Z,12"Z,12"'Z)-tetrakis (octadeca-9,12-dienoate) (OF-Deg-Lin), 3,6-bis(4-(bis(2-hydroxydodecyl)amino)butyl)piperazine-2,5-dione (CKK-E12), l,2-di-(9-octadecenyl-3-trimethylammonium-propane (DOTMA), (6Z,9Z,28Z,3 lZ)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA). In embodiments, the LNP additionally comprises one or more of a PEG-lipid, a sterol structural lipid and / or a neutral lipid. Stabilisers In one embodiment, the present disclosure provides an LNP comprising an ionisable lipid of the present disclosure and a PEGylated lipid or other alternative steric stabilisers. It will be apparent to the skilled person that reference to a PEGylated lipid is a lipid that has been modified with polyethylene glycol. Exemplary PEGylated lipids include, but are not limited to, PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, and PEG-modified dialkylglycerols. For example, a PEG lipid includes PEG2000-DMG, ALC-0159, PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, a PEG-DSPE lipid and combinations thereof. Block copolymers such as reversible addition-fragmentation chain-transfer polymerization (RAFT) polymers containing PEGs, poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and poly(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) groups may also be contemplated, or commercial amphiphilic block copolymers, Pluronics, or poloxamers. In one embodiment, the PEGylated lipid may be PEG-DMG. Alternative stabilisers such as polyvinyl alcohols, polyvinyl pyrrolidones, amphiphilic dairy protein P-Casein, bile salts sucrose stearate may also be used. Neutral lipids In one embodiment, the present disclosure provides an LNP comprising an ionisable lipid compound of the present disclosure and a neutral lipid such as monoolein / phytantriol, other monoacylglycerols. Such lipids to change the interfacial curvature of the LNP resulting in a change of self-assembled nanostructure. Suitable neutral or zwitterionic lipids for use in the present disclosure will be apparent to the skilled person and include, in embodiments, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), l,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3 -phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), l,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (Cl6 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3 -phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, l,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3 -phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3 -phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(l-glycerol) sodium salt (DOPG), and sphingomyelin. The lipids can be saturated or unsaturated. Structural lipids In one embodiment, the present disclosure provides an LNP comprising an ionisable lipid compound of the present disclosure and a structural lipid. Exemplary structural lipids include, but are not limited to, cholesterol, fecosterol, sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, tomatidine, tomatine, ursolic acid and alpha-tocopherol. In one embodiment, the structural lipid is a sterol. In embodiments, the structural lipid is cholesterol. In embodiments, the LNPs comprise an ionisable cationic lipid compound of the present disclosure; a neutral lipid; a sterol such as cholesterol; and a PEGylated lipid. The LNPs are formulated with an agent, such as a nucleic acid to be delivered to a subject. Therapeutic Agent In certain embodiments, the composition further comprises a therapeutic agent, as described herein. For example, in certain embodiments, the agent is a small molecule, organometallic compound, nucleic acid, protein, peptide, polynucleotide, metal, targeting agent, an isotopically labelled chemical compound, drug, vaccine, immunological agent, or an agent useful in bioprocessing. For example, the therapeutic agent is a polynucleotide, peptide, antibody, or small molecule. In certain embodiments, the agent is a polynucleotide. In certain embodiments, the polynucleotide is DNA or RNA. In an embodiment, the polynucleotide is a conventional or selfamplifying mRNA. The ionisable lipids of the present disclosure may form complexes with, and so be formulated into LNPs with, a range of nucleic acids including, but not limited to, a messenger RNA (mRNA), a single guide RNA (sgRNA), a guide RNA (gRNA), a self-amplifying mRNA (sa-mRNA), a small interfering RNA (siRNA), antisense oligonucleotide, plasmid DNA (pDNA), microRNA (miRNA), miRNA inhibitors (antagomirs / antimirs), messenger-RNA-interfering complementary RNA (micRNA), DNA, multivalent RNA, dicer substrate RNA, complementary DNA (cDNA), and the like. In this manner the LNPs and compositions may, in some embodiments, be used to induce expression of a desired protein both in vitro and in vivo by contacting cells with an LNP comprising one or more novel ionisable lipids of the present disclosure, wherein the LNP encapsulates or is associated with a nucleic acid that is expressed to produce the desired protein, such as a mRNA or plasmid encoding the desired protein. In alternative embodiments, the LNPs and compositions may be used to decrease the expression of target genes and proteins in vitro or in vivo by contacting cells with an LNP comprising one or more novel ionisable lipids of the present disclosure, wherein the LNP encapsulates or is associated with a nucleic acid that reduces target gene expression or is used to silence genes, such as RNAi, CRISPR, or siRNA. Therefore, in some embodiments, the nucleic acid is a mRNA encoding a polypeptide of interest, including any naturally or non-naturally occurring or otherwise modified polypeptide. A polypeptide encoded by an mRNA may be of any size and may have any secondary structure or activity. In some embodiments, a polypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell. In some embodiments, the present disclosure provides lipid nanoparticle (LNP) conjugates comprising one or more ionisable lipids of Formula I, Formula IA, Formula IB, Formula IC, or Formula ID as appropriate. The LNP may comprise a single such compound or a mixture of two or more ionisable lipids selected from these formulae. In certain embodiments, the compound(s) are chemically attached to a therapeutic agent. In other embodiments, the compound(s) are non-covalently associated, for example through hydrogen bonding, with such an agent. In some embodiments, the therapeutic agent is selected from mRNA, a small molecule, a peptide, or an antibody. For example, the ionisable lipids(s) of Formula I or Formula IA-ID may be covalently conjugated to an mRNA sequence, optionally via a linker group. In other embodiments, the ionisable lipids(s) may be hydrogen bonded to an mRNA sequence within the LNP. In some embodiments, the compound ionisable lipids(s) are conjugated to a small molecule therapeutic. In other embodiments, the ionisable lipids(s) are conjugated to a peptide, such as a targeting peptide. In further embodiments, the ionisable lipids(s) are conjugated to an antibody or antibody fragment. In some embodiments, the LNP conjugates may include combinations of ionisable lipids of Formula I and Formulae IA-ID associated with more than one therapeutic agent, for example a conjugate comprising both an mRNA and a peptide. Lipid Nanoparticle Compositions The LNPs comprising an ionisable lipid of the present disclosure and a nucleic acid can be formulated for administration via any accepted mode of administration of lipid particles including LNPs, liposomes, lipid vesicles and like lipid-based particles such as monoolein / phytantriol, other monoacylglycerols. Such lipids to change the interfacial curvature of the LNP. The present disclosure is directed to a method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing any of the foregoing LNPs and / or administering a composition comprising the same to the patient. In some embodiments, the therapeutic agent is effective to treat the disease. For the purposes of administration, the lipid nanoparticles as described herein may be administered alone or may be formulated as pharmaceutical compositions. Pharmaceutical compositions of some embodiments comprise a lipid nanoparticle according to any embodiment described herein and one or more pharmaceutically acceptable carrier, diluent or excipient. The lipid nanoparticle may be present in an amount which is effective to deliver the therapeutic agent, e.g., for treating a particular disease or condition of interest. Appropriate concentrations and dosages can be readily determined by a person skilled in the art. Administration of the lipid nanoparticles of some embodiments can be carried out via any of the accepted modes of administration of lipid particles including LNPs, liposomes, lipid vesicles and like lipid-based particles such as monoolein / phytantriol, other monoacylglycerols. Such lipids to change the interfacial curvature of the LNP. The pharmaceutical compositions of some embodiments may be formulated into preparations in solid, semi-solid, liquid forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrastemal injection or infusion techniques. Pharmaceutical compositions of some embodiments are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that may be administered to a subject or patient may take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container comprising LNPs in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art. The composition to be administered will typically contain a therapeutically effective amount of a lipid nanoparticle of any of the embodiments disclosed herein, comprising a therapeutic agent, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest. A pharmaceutical composition of some embodiments may be in the form of a solid or liquid. In some embodiments, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. In other embodiments, the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration. In general terms, by “carrier” is meant a solid or liquid filler, binder, diluent, encapsulating substance, emulsifier, wetting agent, solvent, suspending agent, coating or lubricant that may be safely administered to any subject, e.g., a human. Depending upon the particular route of administration, a variety of acceptable carriers, known in the art may be used, as for embodiment described in Remington's Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991). When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid. As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent. When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil. The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present ionisable lipids, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included. The liquid pharmaceutical compositions of some embodiments, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose; agents to act as cryoprotectants such as sucrose or trehalose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile. When the pharmaceutical composition is a vaccine composition then the carrier may be water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g phosphate, citrate etc. buffered solutions. In some embodiments of a vaccine, one or more compatible solid or liquid fillers or diluents or encapsulating compounds may be employed which are suitable for administration to a person. Pharmaceutically acceptable carriers, fillers and diluents will have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a subject. Some examples of compounds which can be used as pharmaceutically acceptable carriers, fillers or constituents thereof are sugars, such as, for example, lactose, glucose, trehalose and sucrose; starches, such as, for example, com starch or potato starch; dextrose; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, com oil and oil from theobroma; polyols, such as, for example, 73 polypropylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; and alginic acid. When the pharmaceutical composition is a vaccine composition it may further comprise one or more pharmaceutically acceptable adjuvants to enhance the immunostimulatory properties of the composition. The adjuvant may be any compound, which is suitable to support administration and delivery of the LNP composition and which may initiate or increase an immune response of the innate immune system, i.e. a non-specific immune response. A liquid pharmaceutical composition of certain embodiments intended for either parenteral or oral administration should contain an amount of a lipid nanoparticle of the invention such that a suitable dosage will be obtained. The pharmaceutical composition of embodiments of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. The pharmaceutical composition of some embodiments may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable non-irritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. The pharmaceutical composition of other embodiments may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule. The pharmaceutical composition of embodiments in solid or liquid form may include an agent that binds to the LNP or therapeutic agent and thereby assists in the delivery of the LNP or therapeutic agent. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, or a protein. In other embodiments, the pharmaceutical composition may comprise or consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. A person skilled in the art, without undue experimentation may determine preferred aerosols. In some embodiments, the pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the lipid nanoparticles as described herein with sterile, distilled water or other carrier so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system. The pharmaceutical compositions of some embodiments are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific therapeutic agent employed; the metabolic stability and length of action of the therapeutic agent; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. The pharmaceutical compositions of various embodiments may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation of a composition of the invention and one or more additional active agents, as well as administration of the composition of the invention and each active agent in its own separate pharmaceutical dosage formulation. Where separate dosage formulations are used, the ionisable lipids of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens. Preparation methods for the above ionisable lipids and compositions are described further herein and / or are known in the art. In general, LNPs are synthesized by mixing under pressure and flow an aqueous phase containing a nucleic acid (e.g. mRNA) with an organic (e.g. ethanol) phase. For example, the aqueous phase may be prepared with or without buffer with the corresponding mRNA. The organic phase may be prepared by solubilizing a mixture of ionisable compound as described herein, phospholipid, cholesterol, lipid-anchored PEG, and additives at predetermined molar ratios. For the Lipopolysaccharide (LPS) containing formulations, the LPS can be added to the organic phase as a solution in a solvent (e.g. DMSO) (1 mg / mL; Lipopolysaccharide), for example. The organic and aqueous phases may be mixed at a 3:1 ratio, for example, in a microfluidic chip device. The resulting LNPs can be dialyzed against PBS at room temperature to provide the lipid nanoparticles (LNPs). The particles can be manufactured using various methods including jet mixing, impingement jet mixing, microfluidics, extrusion, homogenisation, resonant acoustic mixing, ultrasonication, vortex mixing and other means known to those skilled in the art. It will be appreciated that the ratio of PEGylated lipid, ionisable lipid, neutral lipid and structural lipid in a LNP can be changed depending on the components of the LNP and the particular application. The efficiency of encapsulation of the polynucleotide within the LNPs comprising a compound of the present disclosure may be at least 50%, for example about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the encapsulation efficiency may be at least 50%. In certain embodiments, the encapsulation efficiency may be at least 75%. The encapsulation efficiency of the polynucleotide within the LNPs can be measured by any suitable means known in the art. For example, the encapsulation efficiency of the polynucleotide within the LNPs comprising a compound of the present disclosure as described herein can be measured using a RiboGreen assay. Methods of Treatment Diseases, disorders, and / or conditions which may be a result of or related to aberrant protein or polypeptide may be treated by the present LNPs comprising a compound of the present disclosure and a polynucleotide and may include, but are not limited to, rare diseases, infectious diseases, cancer and proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and renovascular diseases, and metabolic diseases. LNP compositions may be formulated in dosage unit form. The therapeutically effective or prophylactically effective dose for any particular patient will depend upon a variety of factors including the severity and identify of a disorder being treated; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific pharmaceutical composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific pharmaceutical composition employed; and like factors well known in the medical arts. LNP compositions described herein may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. They may be administered together in a single composition or administered separately in different compositions. In some embodiments, the present disclosure provides for the use of the LNPs comprising an ionisable lipid of the present disclosure and a polynucleotide in the manufacture of a medicament for the treatment of a disease, disorder or condition. The disease, disorder or condition may be as described in any one or more embodiments 5 herein. The medicament may be for the prevention or treatment of a cancer, an infectious disease, a genetic disease, an allergy, or an autoimmune disease. It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing 10 from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. EXAMPLES Example 1: Synthesis of ionisable lipids The exemplary syntheses of ionisable lipids of the present invention are shown 15 below. The synthetic approach would be understood by a person of skill in the art to be readily applicable to other ionisable lipids of the present invention. Simple modifications of conditions or use of a particular substrate may be changed to achieve any ionisable lipid within the scope of Formula I, Formula IA, Formula IB, Formula IC, and Formula ID. General procedure Method 1: Alkylation Method: 5.4 mmol of 1, 5.4 mmol of 2 (1 eq.), and 10.8 mmol of potassium carbonate 5   (2 eq.) was dissolved in acetonitrile and heated to 90 °C and stirred overnight. The mixture was then allowed to cool to room temperature and then extracted with diethyl ether and washed with water. The organic layer was collected and dried over magnesium sulfate and filtered. The solvent was then evaporated, and the Lipid 3 was purified via column chromatography with DCM / Methanol as the eluent. 10            It will be appreciated that Lipids 1-4 were prepared using Method 1. Method 2: Reductive Amination Method: 1 mmol of 1, 5 mmol of 2 (5 eq.), 5 mmol of acetic acid (5 eq.) was dissolved in ethyl acetate and stirred at room temperature. To this solution 5 mmol (5 eq.) of 15 sodium triacetoxyborohydride was added. The mixture was then stirred at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with a solution of sodium bicarbonate. The organic layer was collected and dried over magnesium sulfate and filtered. The solvent was then evaporated, and the Lipid 3 was purified via column chromatography with DCM with 5% ethyl acetate / Methanol as the eluent. It will be appreciated that Lipids 5-86 were prepared using Method 2. Example 2: Formulation of ionisable lipids into LNPs with a mRNA General procedure To encapsulate EGFP mRNA within lipid nanoparticles (LNPs), two solutions were prepared: • Solution 1 (aqueous phase) was prepared by diluting mRNA with 10 mM Sodium Citrate buffer at pH 4.0, achieving a concentration of approximately 133 pg / mL; and • Solution 2 (organic phase) was prepared by dissolving a combination of an ionizable lipid of the present disclosure, cholesterol, and either DSPC or DOPE, andPEG-DMGin 100% ethanol, following molar ratios of 50:38.5:10:1.5 for formulations with DSPC and 25:30:30:1.5 for DOPE respectively. The organic phase was added to the aqueous phase in a 3:1 volume ratio while vigorously mixing using a vortex mixer. This rapid mixing led to supersaturation of lipid molecules and initiated the self-assembly of the LNPs. All LNPs maintained N / P ratios at 6 for DSPC formulations and ratios of 10 for DOPE formulations. LNP’s were prepared with novel ionisable lipids of the present disclosure along with cholesterol, DSPC or DOPE, and PEG-DMG in the ratios described above. Control (Empty) LNPs, were similarly prepared using only the aqueous buffer without mRNA. The solutions were then dialyzed using a Pur-A-Lyzer Midi 3500 Dialysis tube against 1 * TE buffer for at least 1 hour to remove ethanol and adjust the pH. Characterisation ofLNPs The LNPs were characterized for mRNA encapsulation efficiency, particle size, poly dispersity index (PDI), and cellular expression. RiboGreen Assay for %EE measurement: In the context of LNP characterisation, the RiboGreen assay was employed to determine the encapsulation efficiency (EE) of mRNA within LNPs. This measurement is crucial for assessing the potential ofLNPs as mRNA delivery systems, ensuring that a significant proportion of the loaded mRNA is successfully encapsulated and protected within the lipid nanoparticle. This assay revealed that LNPs 1 to 7 comprising lipids 1, 2, 3, 4, 10, 83 and 84, respectively, had efficiencies over 50%, indicating effective encapsulation and protection of mRNA within the lipid nanoparticle, as shown in Figure 1(a). These LNPs hold the potential for use in mRNA delivery systems. Particle Size and PDI: For size and PDI measurements, LNPs were diluted (10 pL LNPs in 900 pL RNase-free water) and analysed using a Malvern Zetasizer Nano ZS. This assay revealed that LNPs 1 to 7 comprising lipids 1, 2, 3, 4, 10, 83 and 84, respectively, had particle sizes ranged between 140-165 nm with a PDI between 0.1 and 0.35, as shown in Figure 1(b), which are typical for particles prepared via vortex mixing. This size range is favourable for the delivery of mRNA vaccines and small molecule drugs. Apparent pKa measurements (TNS assay): The charged state of nanoparticles depends on the pH of the medium, and the changes can be predicted with their apparent pKa. The measurement of pKa may help in understanding the advantages and problems of the nanoparticles in various biological processes distinct pH values. The pKa of these LNPs, measured using a TNS fluorescence assay, ranged from 5.2 to 6.9. LNPs 1 to 5 formulated with lipids 1, 2, 3, 4, and 10, respectively, exhibited pKa values within the optimal range (6-7.8) for mRNA delivery, suggesting enhanced efficiency for RNA delivery applications. SAXS Analysis: Partial phase diagrams of the LNPs were studied using Synchrotron SAXS beamline technology, focusing on the effects of pH on lipid self-assembly. This analysis was performed on the LNPs with >50 % encapsulating mRNA. LNPs 1 to 5 formed with lipids 1, 2, 3, 4, and 10, respectively, along with cholesterol, DOPE, and PEG-DMG, conducted at 25°C. The results indicate the presence of micellar cubic phase (Fd3m) and hexagonal (H2), known for their effective encapsulation and release under acidic conditions, such as those in endosomes (Figure 2). The results from SAXS analysis further prove the application of these novel lipids in the delivery of mRNA. Transfection Efficiency Evaluation The prepared LNPs were screened for their transfection efficiency using HEK293 cell lines. The mRNA-loaded LNPs were compared against an in-house Moderna formulation using ionizable lipid SM-102 as a positive control (Control - as depicted below). OH 0 'S             O x               A - -v M       - JI A -       . O"                                    '0" Of the tested LNPs, those prepared using lipids 1, 4, and 10 showed transfection intensities comparable to the in-house Control 1, indicating their potential as effective mRNA delivery vehicles (Figure 3). Additionally, LNPs prepared using lipids 2 and 3, though less effective, still produced detectable levels of GFP protein, suggesting some degree of transfection capability. In vitro assessment of Lipid Nanoparticles In vitro evaluation of LNPs was performed using HEK-293 and Jurkat cells. HEK-293 cells were maintained in DMEM culture medium supplemented with 10% heat inactivated FBS, 2 mM 1-glutamine (GlutaMAX), 1% NEAA. Jurkat cells were maintained in RPML1640 with 10% heat inactivated FBS and 2mM L-glutamine (GlutaMAX). All cells were cultured under standard conditions (37 °C, 5% CO2). Prior to treatment, cells were serum-starved overnight to synchronise populations. For screening, HEK-293 cells were seeded in 96-well plates at -70% confluence one day prior to treatment. Jurkat cells were seeded at 5.Ox 104 cells per well in 96 well plates on the day of treatment. LNP formulations containing eGFP-encoding mRNA (GenScript #SC2325, or APEX Bio, Cat#R1016) were prepared according to protocols outlined in the relevant methods section. 100 pg / ml stock LNPs were diluted to 20 pg / ml in PBS immediately before spiking into plates for final concentration of 1 pg / ml. GFP expression in HEK-293 cells was monitored using an Incucyte live-cell imaging system (Sartorius, Incucyte S3-C2). GFP expression was quantified by automated image analysis (Sartorius software, V.2024A), with green fluorescence intensity detected with a fixed threshold across all experiments and normalised to cell confluence to account for differences in cell density, reported as GFP Integrated Intensity (GCU x pm2 / image). Kinetic measurements were collected at 2h intervals over a 48h period, allowing assessment of both transfection efficiency and expression dynamics. Final assessments were made based on 24 and 48h data points. Jurkat cells were treated with LNPs under suspension culture conditions, and GFP expression was assessed 24h post-treatment by flow cytometry using BD Symphony equipped with a high-throughput plate-based sampler. Data were analysed using FlowJo software (V10.10.0) with GFP expression quantified as mean fluorescence intensity (MFI) set according to positive and negative controls. Cytotoxicity of LNPs was assessed using CountBright™ absolute counting beads (Invitrogen, # C36950) to determine absolute live cell counts. Commercially available eGFP mRNA - SMI02 LNP (GenScript, #SC2346) was included as a positive control, while cells treated with 0.125% EtOH (vehicle) were used as negative control across the board. All LNPs were independently tested at least three times.

Claims

1. An ionisable lipid of Formula I, or an ionic form thereof:z I wherein:R1 is selected from C1-6alkyl, C1-6hydroxyalkyl or C1-6alkoxyalkyl;Z is selected from -OR4, -NR4R5, or -SR4;R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6hydroxyalkyl, or C1-6alkoxyalky;orR1 and Z together with the nitrogen to which they are attached join to form a heterocyclic ring selected from an optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrroline, optionally substituted pyrazolidinyl, optionally substituted pyrimidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted azepinyl, optionally substituted diazepanyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl; and wherein the heterocyclic ring forms a compound selected from the group consisting of Formulae IA to ID:wherein X is selected from CR7, N, or O; when X is O, R8 is absent; and when X is CR7 or N, R8 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6alkyl optionally interrupted by -O- and substituted with a C1-6hydroxyalkyl, mono- or di(C1-6)alkylamino, C1-6dialkylaminoalkyl, or heteroaryl; and R7, when present, is selected from the group consisting of hydrogen or C1-6alkyl; wherein Z1, Z2 and Z3, Z4 and Z5, when present, are each independently selected from CR9 or NR9; R9 is independently selected from hydrogen, C1-6alkyl, or C1-6hydroxyalkyl; wherein the heterocyclic ring of Formulae IA to ID comprises (a) no additional heteroatoms, (b) one additional heteroatom, or (c) two additional heteroatoms, wherein said additional heteroatoms are independently selected from nitrogen or oxygen; and optionally, for Formula IC, any two of Z1, Z2, Z3, Z4 and R5 together form a fused 9- or 10-membered non-aromatic bicyclic ring;X1, X2, and X3 are each present, and are either the same or different and independently selected from optionally substituted C7-22alkyl, optionally substituted C7-22alkenyl, optionally substituted C7-22alkynyl, optionally substituted C7-22acyl, or C7-22alkyl or C7-22alkenyl optionally interrupted with at least one of -O-, -S-, -S-S-, -OC(O)-, -C(O)O-, -OC(O)O-, -C(O)NH-, or -NHC(O); wherein each of X1, X2, and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN);each Y is either the same or different and independently selected from -O-, -NR3-, or -S-; andR3 is selected from the group consisting of hydrogen and C1-6alkyl;with the proviso that (a) when R1 and Z together with the nitrogen to which they are attached join to form a piperazine or pyrrolidine, the piperazine or pyrrolidine is not substituted with a carbonyl-containing group, a phenyl group, or a benzyl group, and (b) when any of X1, X2, X3 comprises an uninterrupted methylene (-CH2-) portion, that uninterrupted portion consists of from 2 to 16 methylene units.

2. The ionisable lipid of claim 1, wherein R1 is selected from -CH3, -(CH2)2OH,or-(CH2)2OCH3.

3. The ionisable lipid of claim 1 or claim 2, wherein Z is selected from -OH,OCH3, -OCH2CH2OH, -NHCH3, -N(CH3)2, or -N(CH2CH3)2.

4. The ionisable lipid of any one of the preceding claims, wherein Y is O andeach of X1, X2, and X3 are either the same or different and independently selected from substituted C7-20alkyl, optionally substituted C7-11alkyl, optionally substituted C8-10alkyl, or C7-22alkyl or C7-22alkenyl optionally interrupted with at least one of -O-, -S-, -S-S-, -OC(O)-, -C(O)O-, -OC(O)O-,-C(O)NH-, or -NHC(O); wherein each of X1, X2, and X3 terminates with a group selected from: a primary, secondary or tertiary alkyl group; an alkene group; an alkyne group; an aromatic ring; a cycloalkyl ring having 6 to 9 carbon atoms; hydroxyl (-OH); or a cyano (-CN).

5. The ionisable lipid of any one of the preceding claims wherein each of X1, X2,and X3 are either the same or different and independently selected from a compound of Formula a2:r Mi                 F Formula a2wherein: ■    ■ denotes the attachment point to Y; Mi and M2 is absent orpresent, and when present is selected from the group consisting of, -O-, -S-, -S-S-, -OC(O)-, -C(O)O-, -OC(O)O-, -C(O)NH-, and -NHC(O)-; D and F are each independently an optionally substituted linear or branched Ci-i6alkyl; E is absent or present, and when present represents a divalent group of formula's wherein ’ - ' denotes the attachment point to Y denotes the attachment points to Y, Mi, D or M2 at one end and F at the other end; G is selected from the group consisting of hydroxy (-OH), cyano (-C=N), Ci-6alkyl, C3-i2cycloalkyl, C2-6alkenyl, C2-6alkynyl, bicyclic hydrocarbon groups, aryl, or heteroaryl; and r and s are each independently an integer from 0 to i0.

6. The ionisable lipid of any one of the preceding claims, wherein Y is -O- andeach of X1, X2, and X3 are either the same or different and independently selected from a compound of Formula a2:Formula a2wherein: ■    ■ denotes the attachment point to Y; Mi and M2 is absent orpresent, and when present is selected from the group consisting of -O-, -OC(O)-, -C(O)O-, -OC(O)O-; D and F are each independently an optionally substituted linear or branched Ci-i6alkyl; E and s are absent; G is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, methoxy, C2-6 alkenyl, C2-6 alkynyl, cyclohexyl, substituted or unsubstituted norbornenyl, aryl, heteroaryl or -C=N; and r is an integer from 2 to 8.

7. The ionisable lipid of claim 6, wherein each of Xi, X2, and X3 are either thesame or different and independently selected from the groups consisting of Formulae a2-i to a2-49:Formula a2-i;Formula a2-2;Formula a2-3;Formula a2-4;Formula a2-5;Formula a2-6;Formula a2-7;Formula a2-8;Formula a2-9;Formula a2-10;OHFormula a2-11;Formula a2-12;Formula a2-13;Formula a2-14;Formula a2-16;Formula a2-15;Formula a2-17;0Formula a2-18;0Formula a2-19;Formula a2-20;Formula a2-21;Formula a2-22;          Formula a2-23;Formula a2-24;Formula a2-25;Formula a2-26;0Formula a2-27;0Formula a2-28;Formula a2-29;0Formula a2-30;0Formula a2-31;Formula a2-32;Formula a2-33;Formula a2-34;Formula a2-35;Formula a2-36;Formula a2-37;Formula a2-38;Formula a2-39;Formula a2-40;Formula a2-41;Formula a2-42;Formula a2-43;Formula a2-44;0Formula a2-45;Formula a2-46;Formula a2-47;Formula a2-48;Formula a2-49;wherein: ■    ■ denotes the attachment point to Y.

8. The ionisable lipid of claim 1, selected from the group consisting of:H,C H,C         / c:hj Ti HO .-. J - rr I Ah Lipid 1 HjC -CHj HjC CH3     ( L^ch3 / ” CHj rA:n3 -CHj J \ / „0' HO^^. J "" N OH Lipid 3HjC H>c. 7 CH, \ 0 / L X Lipid 2 h3g -CHj HjC CHj CHj f^CHi -c:Hj J L.ch3 / " ' 1 C p*CH3 / r hsc'J OH Lipid 4ch3 h3c^ / CH3          /       h3cVCH3 O                 0 h3c, ) 3 N ch3 ch3 Lipid 9 h3c ) h3c.            \           ch3 H3c. ) 3 N h3c ch3 Lipid 10 h3c H>cy-CHS     ^G"3  h,g^-ch’ I b ? V  0>° °Yb / ° H3%J rN^ ^^3^^3                Lipid 11 ch3 CH.      < <„             Hb H3Ck ) 3 N ch3 ch3 Lipid 12Lipid 13Lipid 14Lipid 15Lipid 16Lipid 26Lipid 25Lipid 27Lipid 28p l_l           0H3 Ph3        / 3   h3c \       )=0     / 0= /      0 0 \        /          / =0 p     \      o / 0 ) O\^L / O OCH3 Lipid 29 pi-i           OH3 ,oh3         / 3   H3C \       )=0     / n= /      0      v_ 0 \        /          / =0 p \ <r / 0 5 h3co^nJ och3 Lipid 30 ch3 HA        S         CH3 \       0      J /        0=(           1 v     °^° 0        \       0 /     0     \ O'yA^x'° / h3c. ) 3 N ch3 ch3 Lipid 31 H3C ch3              (          h3c / \ \      0=(         / °yo ^0  o^° 0        \       0 / 0 \ O^X / O icr h3%J rN^i ch3 ch3 Lipid 329.       The ionisable lipid of claim 1, selected from the group consisting of:Lipid 34Lipid 35OH                        Lipid 36h3c-noH3             Lipid 37Lipid 38Lipid 39Lipid 41Lipid 40h3c h3c         /      ch3 o,a,o Her Lipid 42 h3c >-ch3 h3c^,ch3     (          ch3 L       (       p  ch3 1        )—ch3 J VH3 \ i L     / c^ch3 1 ° J l^'N^ h3c. J 3 N ch3 Lipid 43 Ck yo y o j HN^J Lipid 44 H3c h3c        /      ch3 / ° \ YjT HO^OJ Lipid 45Lipid 46Lipid 47CM       CH3 / H3        /      H3C \       )=0     / r>= /       0       \ 0 \        /          / =0 9      \       0 / 0 / OyL / O7 HN^J Lipid 48 h3c )—ch3 h3c^.ch3     (          ch3 L     (     Ach3 1          / —ch3 J vCH3 \      [ y   r'CH3 1 0 J o^A^cr inr l^'N^ HO^ Lipid 49 ch3 \      H3C h3c            /       ) / °=\       ( 7^°   °\       / =° O^X^O IM '—1              Lipid 50 CM       CH3 / H3        /      H3c \       )=0    / n= /      0 0 \       I          / =0 9      \       0 / 0 / Ox / 'k^O Lipid 51Lipid 52Lipid 53Lipid 54h3c-\ch3                 Lipid 55Lipid 56Lipid 57Lipid 58Lipid 59Lipid 61Lipid 60Lipid 62Lipid 63Lipid 65Lipid 64OHLipid 67Lipid 66Lipid 68OHLipid 69Lipid 70Lipid 710HOLipid 75OHLipid 74ch3 ch3 H3C 0=( )=0 0 )=0 0 / 0 0. 0    2 0^ Lipid 76 ch3 ch3 H3C O=( )=° O / =0 0 / 0 0, o7 \ h3co^^ Lipid 78ch3 ch3 H3C 0=( )=0 0 )=0 0 0 H3C. 3 Y N °\^ ch3 0   2 0 Lipid 77 ch3 ch3 H3c 0=( )=0 0 )=0 0 ex YN h3co^ o7 \ 0 Lipid 79Lipid 80Lipid 81Lipid 82Lipid 83H3C h3c         /      ch3 \ o / H C'N^ Lipid 84 H3C H3C          /       CH;, °'T^r° HCr Lipid 85 h3c HSC         /      ch3 o i □ Lipid 8612.     The lipid nanoparticle of claim 11, wherein the therapeutic agent is apolynucleotide, peptide, antibody, or small molecule.

13. The lipid nanoparticle of claim 12, wherein the polynucleotide is selected fromthe group consisting of: a messenger RNA (mRNA), a single guide RNA (sgRNA), a guide RNA (gRNA), a self-amplifying mRNA (sa-mRNA), a small interfering RNA (siRNA), a microRNA (miRNA), miRNA inhibitors (antagomirs / antimirs), messenger-RNA-interfering complementary RNA (micRNA), short hairpin RNA (shRNA), multivalent RNA, dicer substrate RNA, an antisense oligonucleotide, plasmid DNA, DNA (pDNA), and complementary DNA (cDNA).

14. A LNP conjugate wherein the ionisable lipids of any one of claims 1 to 9 arechemically attached or hydrogen bonded to a mRNA, small molecule, peptide or antibody.

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