Ionizable lipid and use thereof

Abstract

The present invention relates to a novel ionizable lipid compound represented by formula (I), or a salt thereof, and lipid nanoparticles comprising same. The lipid nanoparticles comprising the novel ionizable lipid compound, according to the present invention, have excellent nucleic acid encapsulation efficiency and high nucleic acid cell delivery efficiency.

Description

Ionized lipids and their uses The present invention relates to a novel ionizable lipid or salt thereof, a lipid nanoparticle comprising the ionizable lipid or salt thereof, and a composition comprising an ionic drug and the ionizable lipid or salt thereof or the lipid nanoparticle. With the development of biotechnology, active research is being conducted to prevent or treat diseases by delivering nucleic acids such as RNA interference therapeutics, antisense oligonucleotides (ASOs), short interfering RNA (siRNA), aptamers, messenger RNA (mRNA), self-amplifying RNA (SAM), and circular RNA into the body. Meanwhile, nucleic acids have the disadvantage of being easily degraded by body enzymes such as RNase and nuclease in the blood. In addition, among nucleic acids, mRNA with a length of more than 500 nucleotides has a large molecular weight of more than 200 KDa, making it difficult to deliver nucleic acids to target cells in the body. In addition, the negative charge characteristic of nucleic acids is a factor that hinders the delivery of nucleic acids to target cells in the body. Therefore, the importance of lipid nanoparticles (LNPs) as drug delivery vehicles to facilitate delivery of nucleic acids to target cells while preventing nucleic acid degradation in the body is increasing. In fact, recently, an mRNA-based COVID-19 virus vaccine (Spikevax) TM , Comirnaty TM ) LNP was also used during the development process. LNPs are generally known to be composed of ionizable lipids, helper lipids such as phospholipids, cholesterol, and PEG-lipids. The ionizable lipids that make up LNPs are generally composed of an ionizable head, a linker, and a terminal consisting of a hydrocarbon chain. They are known to play a key role in determining the efficiency of nucleic acid delivery by electrostatically binding to nucleic acids, encapsulating them, and enabling their escape from endosomes within cells. In addition, cholesterol keeps LNP particles rigid and stable, and PEG-lipids prevent aggregation between LNP particles and ensure structural stability. Furthermore, helper lipids (e.g., phospholipids) play a role in maintaining the lipid bilayer structure of LNP particles. [Prior Art Literature] (Patent Document 1) US Patent Publication No. US 2020 / 0140378 A1 The purpose of the present invention is to provide a novel ionizable lipid compound or salt thereof having excellent nucleic acid delivery efficiency and nucleic acid encapsulation efficiency while minimizing nucleic acid degradation, lipid nanoparticles containing the same, and a composition for drug delivery. The present inventors synthesized and manufactured a novel ionizable lipid compound by introducing a diazabicyclo structure to the head portion of an ionizable lipid, adding an ester group or a branched ester group to the terminal hydrocarbon chain of the ionizable lipid, or further repeatedly substituting the ester group with another group, and discovered that LNPs including the novel ionizable lipid have excellent nucleic acid encapsulation efficiency and nucleic acid cell delivery efficiency, thereby completing the present invention. The novel ionizable lipid compound or salt thereof of the present invention has a diazabicyclo structure, particularly, in the head portion of the ionizable lipid By introducing the structure, it was shown that the homogeneity of particle size such as Z-average diameter, polydispersity index (PDI), nucleic acid encapsulation efficiency such as mRNA, and nucleic acid delivery efficacy into cells were similar or superior to other ionizable lipid compounds having a similar structure, such as containing an ester group in the terminal hydrocarbon chain of the ionizable lipid or having a branched ester structure but having a piperazine head portion of the ionizable lipid. In one embodiment of the present invention, the present invention provides a compound represented by formula (I) or formula (IV) or a salt thereof. In another embodiment of the present invention, the present invention provides a lipid nanoparticle comprising a compound represented by formula (I) or formula (IV) or a salt thereof, a helper lipid, cholesterol, and a PEG lipid. In another embodiment of the present invention, the present invention provides a composition comprising an ionic drug and (i) a compound represented by Formula (I) or Formula (IV) or a salt thereof, or a composition comprising an ionic drug and (ii) the lipid nanoparticle. The novel ionizable lipid compound or salt thereof of the present invention exhibits excellent nucleic acid delivery efficiency and in vivo stability, thereby contributing to improved in vivo stability and therapeutic efficacy of nucleic acid therapeutics. The novel ionizable lipid compound or salt thereof of the present invention exhibits a nucleic acid encapsulation efficiency of at least 93% and excellent nucleic acid delivery efficacy into cells. FIG. 1 is a diagram illustrating the z-average diameter and polydispersity index (PDI) of an F1 type LNP comprising any one of Lipid 1 to Lipid 5 and Lipid 8 to Lipid 15, which is an example of the present ionizable lipid compound (i.e., Lipid 1-(F1) to Lipid 5-(F1) and Lipid 8-(F1) to Lipid 15-(F1)) and an F2 type LNP comprising any one of Lipid 1 to Lipid 4 and Lipid 8 to Lipid 15 (i.e., Lipid 1-(F2) to Lipid 4-(F2) and Lipid 8-(F2) to Lipid 15-(F2)). FIG. 2 is a diagram illustrating the encapsulation efficiency of an F1 type LNP comprising any one of Lipid 1 to Lipid 5 and Lipid 8 to Lipid 15, which is an example of the ionizable lipid compound of the present invention (i.e., Lipid 1-(F1) to Lipid 5-(F1) and Lipid 8-(F1) to Lipid 15-(F1)) and an F2 type LNP comprising any one of Lipid 1 to Lipid 4 and Lipid 8 to Lipid 15 (i.e., Lipid 1-(F2) to Lipid 4-(F2) and Lipid 8-(F2) to Lipid 15-(F2)). Figure 3 is a diagram showing the nucleic acid delivery efficiency into cells of the experimental group (LNPs including Lipid 1-(F1), Lipid 1-(F2), Lipid 9-(F1), Lipid 9-(F2), Lipid 11-(F1), Lipid 11-(F2), Lipid 12-(F1), Lipid 12-(F2) or Lipid 15-(F1)), positive control (MC3 LNP) and negative control (free mRNA). Figure 4 is a diagram showing the expression rate of luminescent firefly luciferase protein in the liver of mice when the experimental group (LNP containing Lipid 8-(F2), Lipid 9-(F2), Lipid 10-(F2), Lipid 11-(F2), or Lipid 13-(F2)) and the positive control group (MC3 LNP) were mixed with luminescent firefly luciferase mRNA nucleic acid and administered into the tail vein of mice, or when only PBS (negative control) was administered into the tail vein of mice. Figure 5 is a drawing showing the expression of luminescent firefly luciferase protein in the liver of mice when the experimental group (LNP containing Lipid 8-(F2), Lipid 9-(F2), Lipid 10-(F2), Lipid 11-(F2), or Lipid 13-(F2)) and the control group (MC3 LNP) were mixed with luminescent firefly luciferase mRNA nucleic acid and administered into the tail vein of mice, or when only PBS (negative control) was administered into the tail vein of mice. Figure 6 is a diagram showing the protein expression rate of luminescent firefly luciferase mRNA delivered to the muscle when the experimental group (LNP containing Lipid 3-(F1), Lipid 3-(F2), Lipid 8-(F1), Lipid 8-(F2), Lipid 9-(F1), Lipid 9-(F2), Lipid 10-(F1), Lipid 10-(F2), Lipid 11-(F1), Lipid 11-(F2), Lipid 12-(F1), or Lipid 13-(F1)) and the positive control group (MC3 LNP) were mixed with luminescent firefly luciferase mRNA nucleic acid and administered to the thigh muscle of a mouse, or when only PBS (negative control) was administered to the thigh muscle of a mouse. Figure 7 is a drawing showing the presence or absence of luciferase protein expression in the muscle when the experimental group (LNP including Lipid 3-(F1), Lipid 3-(F2), Lipid 8-(F1), Lipid 8-(F2), Lipid 9-(F1), Lipid 9-(F2), Lipid 10-(F1), Lipid 10-(F2), Lipid 11-(F1), Lipid 11-(F2), Lipid 12-(F1), or Lipid 13-(F1)) and the positive control group (MC3 LNP) were mixed with luminescent firefly luciferase mRNA nucleic acid and administered to the thigh muscle of a mouse, or when only PBS (negative control) was administered to the thigh muscle of a mouse. definition As used herein, the term "aliphatic amine" refers to a linear or branched hydrocarbon functional group having an amine terminal, which may have an aliphatic group having one or more unsaturated regions. The aliphatic amine is a functional group comprising one or more amine groups and one or more aliphatic groups, and includes, but is not limited to, triethylamine, tripropylamine, tributylamine, diisopropylamine, triisopropylamine, triisobutylamine, N,N-diisopropylethylamine, stearylamine, ethylenediamine, propylenediamine, hexamethylenediamine, di(6-aminohexyl)amine, decylamine, undecylamine, dodecylamine, tridecylamine, tetradecylamine, hexadecylamine, octadecylamine, oleylamine, docosylamine, and the like. As used herein, the term “alkyl” means a functional group derived from a straight-chain or branched hydrocarbon, including, but not limited to, methyl, ethyl, N-propyl, i-propyl, N-butyl, i-butyl, t-butyl, N-pentyl, N-hexyl, and the like. Additionally, as used herein, the term "cycloalkyl" refers to a saturated carbocyclic group of carbon atoms having a single ring (e.g., cyclohexyl) as well as multiple fused rings (e.g., norbornyl, adamantyl), including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Also, as used herein, the term "heterocycloalkyl" means a mono- or poly-cyclic ring containing at least one, preferably 1 to 4, heteroatoms O, N or S, and does not include an aromatic ring. Examples thereof include pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, morpholine, piperazine, tetrahydropyridinyl, and the like. As used herein, the term "lipid nanoparticle (LNP)" refers to a structure in which a drug (e.g., a nucleic acid-based drug) is mixed with lipids at room temperature or the like to form a uniform phase, which is then dispersed in an aqueous solution so that the drug exists as a solid solution between lipid crystals. Since the lipid nanoparticles use substances existing in the body, such as phospholipids, lipids, and cholesterol, they are particulate drug delivery vehicles with high bioavailability and affinity, and they enable the release and control of drugs and have high stability against degradation by enzymes, etc. In addition, the lipid nanoparticles are positively charged at acidic pH and can encapsulate RNA, and are neutrally charged at physiological pH and can minimize toxicity. ionized lipid compounds The ionized lipid compound of the present invention may be a compound represented by Formula (I) or Formula (IV) described below, or a salt thereof. [1] The compound of the present invention may be a compound represented by the following formula (I) or a salt thereof: L1-L2-L3-L4-L5 (I) The above L1 and L5 are each independently a group represented by the following formula (II), The above L2 is C 1-12 As linear alkyl, substituted or unsubstituted with a hydroxyl group, wherein L2 is C substituted with a hydroxyl group 1-12 If it is a linear alkyl, formula (I) does not include L1, The above L4 is C 1-12 It is a linear alkyl, The above L3 is a 6-membered heterocyclic amine or an aliphatic amine, and the 6-membered heterocyclic amine or aliphatic amine is C 1-6 is substituted with at least one selected from alkyl, amino group, 3-6 membered saturated or unsaturated carbocyclyl, 3-6 membered saturated or unsaturated carbocycloalkyl, 3-6 membered saturated or unsaturated heterocyclyl, and 3-6 membered saturated or unsaturated heterocycloalkyl, wherein n is an integer of 0 or 1, The above X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, The above Rx′ is hydrogen, linear C1- 25 Alkyl, or branched C3- 25 It is alkyl, The above R1 and R2 are, each independently, linear C1- 30 Alkyl or branched C3- 50 As alkyl, they are the same or different from each other, The above R3 and R4 are each independently linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 As alkoxy, which are the same or different from each other, the linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50Alkyl or C 4-40 Alkoxy is C 1-12 is optionally substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine, The above Rx″ is hydrogen, linear C1- 25 Alkyl, branched C3- 25 Alkyl, 3-6 membered saturated or unsaturated carbocyclyl, 3-6 membered saturated or unsaturated carbocycloalkyl, 3-6 membered saturated or unsaturated heterocyclyl, or 3-6 membered saturated or unsaturated heterocycloalkyl, The above wavy lines indicate the bonding positions, The above heterocyclic amine is a cyclic amine group containing one or more heteroatoms selected from N, S or O, The above carbocyclyl is a cyclic group composed of carbon and hydrogen atoms, The above heterocyclyl is a cyclic group containing one or more heteroatoms selected from N, S or O, The above carbocycloalkyl is a carbocyclyl-linear C1-6 alkyl group or a carbocyclyl-branched C3-6 alkyl group, The above heterocycloalkyl is a heterocyclyl-linear C1-6 alkyl group or a heterocyclyl-branched C3-6 alkyl group, However, the above L3 is not piperazine. [2] In the above [1], L3 may be a 6-membered heterocyclic amine or a 6-membered heterocyclic amine containing two N atoms, and may have a diazabicyclo structure. In particular, L3 of the above formula (I) It could be a structure. [3] In the above [1] to [2], L1 and L5 of the above formula (I) may each independently be a compound or a salt thereof represented by the following formula (III): The above R5 is linear C1- 30 It is alkyl, The above Z1 is -(Rx a ) k -O-, or (Rx a ) k -NH- and the above Rx a is linear C1- 25 is an alkyl, and k is an integer of 0 or 1, The above R6 is linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 As an alkoxy, the linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 Alkoxy is C 1-12 Alkyl, Rx b -C(=O)-O-, Rx b -OC(=O)- or at least one selected from the group consisting of amines, wherein Rx b is hydrogen, linear C1- 25 Alkyl, branched C3- 25 Alkyl, a 3-6 membered saturated or unsaturated carbocyclyl, a 3-6 membered saturated or unsaturated carbocycloalkyl, a 3-6 membered saturated or unsaturated heterocyclyl, or a 3-6 membered saturated or unsaturated heterocycloalkyl, wherein a is an integer of 1 or 2, wherein the cyclyl is a cyclic group composed of carbon and hydrogen atoms, wherein the heterocyclyl is a cyclic group containing one or more heteroatoms selected from N, S or O, wherein the cycloalkyl is a carbocyclyl-linear C1-6 alkyl group or a carbocyclyl-branched C3-6 alkyl group, and wherein the heterocycloalkyl is a heterocyclyl-linear C1-6 alkyl group or a heterocyclyl-branched C3-6 alkyl group. [4] In any one of the above [1] to [3], R5 is linear C2- 30 Alkyl, linear C2- 20 Alkyl or linear C2- 10 is alkyl, and the above Z1 is -(Rx a ) k -O-, and the above k can be an integer of 0. [5] In another aspect of the present invention, the compound of the present invention may be a compound or a salt thereof represented by the following formula (IV): The definitions of L1, L2, X, Y, R3, and R4 of the above formula (IV) are the same as the definitions of L1, L2, X, Y, R3, and R4 of the above formula (I), and n1 and n2 are each an integer from 0 to 12, and n3 is an integer of 0 or 1. [6] In one of the above [1] to [5], the L2 is C 1-6 C substituted with linear alkyl or hydroxyl group 1-6 It may be linear alkyl and / or wherein L4 is C 1-6 It may be a linear alkyl compound or a salt thereof. In addition, the L2 is C 1-3 Linear alkyl, C 3-6 C substituted with linear alkyl, hydroxyl group 1-3 C substituted with linear alkyl or hydroxy groups 3-6 It may be linear alkyl and / or wherein L4 is C 1-3 Linear alkyl or C 3-6 It may be a linear alkyl. In addition, the above L2 is C 3-4 C substituted with linear alkyl or hydroxyl group 3-4 It may be linear alkyl and / or the L4 is C 3-4 It can be a linear alkyl. [7] In any one of the above [1] to [6], X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein Rx′ is hydrogen or linear C1- 25 It can be alkyl. The above X and Y can be -Rx′-C(=O)-O-, and Rx′ is linear C1- 25 It could be an alkyl. [8] In any one of the above [1] to [7], R1 and R2 are each independently linear C1- 30 Alkyl or linear C1- 15 As alkyls, they may be the same or different. [9] In any one of the above [1] to [8], R1 and R2 are each independently linear C1- 12 Alkyl groups may be the same or different.

[0010] In any one of the above [1] to [9], R3 and R4 are, each independently, linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, unsubstituted or C 1-12 It may be substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine.

[0011] In any one of the above [1] to

[0010] , the L2 is C 1-6 C substituted with linear alkyl or hydroxy groups 1-6 Linear alkyl, wherein L4 is C 1-6Linear alkyl, wherein X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein Rx′ is hydrogen, or linear C1- 25 Alkyl, and R1 and R2 are, each independently, linear C1- 30 Alkyl or branched C3- 50 As alkyl, which are the same or different from each other, R3 and R4 are, each independently, linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, which are the same or different from each other, the linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 Alkoxy is unsubstituted or C 1-12 It may be substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine.

[0012] In any one of the above formulas [1] to

[0011] , L3 of the formula (I) has a diazabicyclo structure, and L2 is C 1-4 C substituted with linear alkyl or hydroxy groups 1-4 Linear alkyl, wherein L4 is C 1-6 Linear alkyl, wherein X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein Rx′ is hydrogen, or linear C1- 12 Alkyl, wherein R1 and R2 are each independently linear C2-8 alkyl and are the same or different from each other, and wherein R3 and R4 are each independently linear C1- 20 Alkyl, linear C1-20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, which are the same or different from each other, the linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 Alkoxy is unsubstituted or C 1-12 It may be substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine. In addition, the above L3 has a diazabicyclo structure, and the above L2 has C 1-4 Linear alkyl, wherein L4 is C 1-4 Linear alkyl, wherein X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein Rx′ is hydrogen, or linear C1- 12 Alkyl, wherein R1 and R2 are each independently linear C2-8 alkyl and are the same or different from each other, and wherein R3 and R4 are each independently linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, which are the same or different from each other, the linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 Alkoxy is unsubstituted or C 1-12 It may be substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine. Additionally, the L3 has a diazabicyclo structure, and the L2 is C substituted with a hydroxy group. 1-4 Linear alkyl, wherein L4 is C1-6 Linear alkyl, wherein X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein Rx′ is hydrogen, or linear C1- 12 Alkyl, wherein R1 and R2 are each independently linear C2-8 alkyl and are the same or different from each other, and wherein R3 and R4 are each independently linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, which are the same or different from each other, the linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 Alkoxy is unsubstituted or C 1-12 It may be substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine.

[0013] In any one of the above [1] to

[0012] , the compound of the present invention may be a compound or a salt thereof selected from the following group: (1)((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetranonanoate; (2) Tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (3) Tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (4) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetraheptanoate; (5) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(ethane-2,1-diyl)tetraheptanoate; (6) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetratridecanoate; (7) Tetrakis(2-ethylhexyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (8) Tetrakis(2-ethylhexyl) 6,6',6'',6'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrahexanoate; (9) Tetrakis(2-propylhexyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (10) Tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (11) Tetrakis(2-ethylpentyl) 6,6',6'',6'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrahexanoate; (12) Tetra((Z)-non-2-en-1-yl) 9,9',9'',9'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate; (13) (((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl)octahexanoate; (14) di(henicosan-10-yl) 3,3'-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; and (15) ((3,3'-((3-(5-(3-hydroxypropyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl)azanediyl)bis(propanoyl))bis(oxy))bis(hexane-6,1-diyl)bis(2-hexyldecanoate). The ionizable lipid compounds of the present invention may have an asymmetric center, a chiral axis and a chiral plane, and may appear as racemates, racemic mixtures and individual diastereomers, wherein all possible isomers and mixtures thereof, including optical isomers, are encompassed by the present invention. A compound such as a compound of formula (I) or formula (IV) or a salt thereof can be prepared by the method shown in the following reaction scheme 1, 2 or 3, but is not limited to those prepared by such methods. Reaction formulas 1 to 3 show the manufacturing method of representative compounds according to the present invention in each manufacturing step. Various compounds of the present invention can be manufactured by changing the reagents and solvents used in the manufacturing steps below or changing the reaction order. [Reaction Formula 1] [Correction pursuant to Rule 91, December 2024] R: linear alkyl, branched alkyl or oxycarbonyl alkyl ET3N: triethylamine DMAP: 4-dimethylaminopyridine DCM: dichloromethane DMF: Dimethylformamide ACN: Acetonitrile Triethylamine and 4-dimethylaminopyridine are sequentially added to a mixed solution of dichloromethane and diol. Then, compound A is added at 0°C, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture is purified to obtain compound B. Triethylamine is added to a mixed solution of dichloromethane and compound B, and acryloyl chloride is added at 0°C. The mixture is stirred at room temperature for 2 hours, and after completion of the reaction, the reaction mixture is purified to obtain compound C. Potassium carbonate (K2CO3) and compound E are added to a mixed solution of dimethylformamide and compound D at room temperature. The mixture is stirred at 70°C for 16 hours, and after completion of the reaction, the reaction mixture is purified to obtain compound F. Hydrazine hydrate is added to a mixed solution of methanol and compound F at room temperature, and the mixture is stirred at room temperature for 48 hours. After the reaction is completed, the reaction mixture is purified to obtain compound G. Hydroquinone is added to a mixed solution of compound G, acetonitrile, and compound C at room temperature. The reaction mixture is stirred at 70°C for 48 hours, and after the reaction is completed, the reaction mixture is purified to obtain the compound of formula (I). The progress of individual reactions according to reaction scheme 1 can be monitored by TLC. [Reaction Formula 2] [Correction pursuant to Rule 91, December 2024] R: linear alkyl, branched alkyl or oxycarbonyl alkyl Benzaldehyde and molecular sieves are added to a mixed solution of ethanol and compound G, and the mixture is stirred at room temperature for 1 hour. Sodium borohydride (NaBH4) is added to the reaction mixture at 0°C, and the mixture is stirred for 16 hours. The reaction mixture is purified to obtain compound J. Separately, triethylamine and 4-dimethylammoniopyridine are added to a mixed solution of dichloromethane and compound H, and compound A is added at 0°C. The mixture is stirred at room temperature for 2 hours, and after the reaction is completed, the reaction mixture is purified to obtain compound I. Compound J and hydroquinone in acetonitrile are added to a solution of Compound I at room temperature. The reaction mixture is stirred at 70°C for 72 hours. After the reaction is complete, the reaction mixture is purified to obtain Compound K. Ethyl acetate and palladium / carbon (Pd / C) are added to a mixed solution of methanol and Compound K, and the mixture is stirred for 2 hours under hydrogen gas balloon pressure (60 psi) and room temperature. After the reaction is complete, the reaction mixture is purified to obtain Compound L. Paraformaldehyde and acetic acid are added to a mixed solution of methanol and Compound L, and the mixture is stirred at room temperature for 2 hours. Sodium cyanoborohydride (NaCNBH3) is added, and the mixture is stirred at room temperature for 16 hours. After the reaction is complete, the reaction mixture is purified to obtain the compound of Formula (I). The progress of individual reactions proceeding according to Scheme 2 can be monitored by TLC. [Reaction Formula 3] [Correction pursuant to Rule 91, December 2024] R: linear alkyl, branched alkyl or oxycarbonyl alkyl Potassium carbonate and compound E are added to a mixed solution of dimethylformamide and compound M at room temperature, and the mixture is stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture is purified to obtain compound N. 1,4-dioxane-HCl (4M solution) is added to a mixed solution of dichloromethane and compound N at room temperature, and the mixture is stirred for 4 hours. After completion of the reaction, the reaction mixture is concentrated to obtain compound O. Potassium carbonate and compound P are added to a mixed solution of dimethylformamide and compound O at room temperature, and the mixture is stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture is purified to obtain compound Q. Hydrazine hydrate is added to a mixed solution of methanol and compound Q, and the mixture is stirred at room temperature for 48 hours. After completion of the reaction, the reaction mixture is purified to obtain compound R. Compound C and hydroquinone dissolved in acetonitrile are added to the solution of compound R at room temperature. The mixture is stirred at 70°C for 72 hours. After the reaction is completed, the reaction mixture is purified to obtain compound S. 1,4-dioxane hydrochloric acid is added to a mixed solution of dichloromethane and compound S at 0°C, and the mixture is stirred at room temperature for 2 hours. After the reaction is completed, the reaction mixture is purified to obtain the compound of formula (I) or (IV). The progress of individual reactions proceeding according to scheme 3 can be monitored by TLC. In the process of preparing compounds of formula (I) or (IV) in the above reaction schemes 1 to 3, the purification of compounds B to S formed may be performed using one or more combinations of methods used in the art to purify compounds, such as filtration (e.g., celite filtration), extraction (e.g., extraction using ethyl acetate or dichloromethane), chromatography (e.g., preparative liquid chromatography (prep-HPLC), NH-silica gel (100 to 200 mesh) column chromatography), etc. In addition, the compounds of formula (I) or (IV) prepared in the above reaction schemes 1 to 3 may be separated and purified using one or more methods used in the art to separate and purify compounds, such as recrystallization, chromatography, etc. lipid nanoparticles In one aspect of the present invention, the present invention may be a lipid nanoparticle comprising the ionizable lipid compound or a salt thereof, a helper lipid, cholesterol, and a PEG lipid. The helper lipid may be a phospholipid. The phospholipid is a lipid comprising a phosphate group and one or more fatty acid chains, may contain one or more multiple bonds, and may interact with one or more negatively charged phospholipids of a membrane (e.g., a cell membrane). The phospholipid may be used without limitation as long as it is a phospholipid capable of promoting fusion of the lipid nanoparticle.As the phospholipids, DOPE (dioleoylphosphatidylethanolamine; 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DSPC (distearoylphosphatidylcholine), POPC (palmitoyloleoylphosphatidylcholine; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), EPC (egg) phosphatidylcholine), DOPC (dioleoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPG (dipalmitoylphosphatidylglycerol), DSPE (distearoylphosphatidylethanolamine), PE (phosphatidylethanolamine, DPPE (dipalmitoylphosphatidylethanolamine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), One or more phospholipids selected from the group consisting of DOPS (1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]), 1,2-dioctadecanoyl-sn-glycero-3-phosphoserine (DSPS; 18:0 PS), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (DOPS; 18:1 PS), sphingomyelin, etc. may be used, preferably at least one selected from DSPC, DOPC, DSPE, DOPE, or sphingomyelin, but is not limited thereto. The PEG lipid may include a lipid directly conjugated to PEG or linked to PEG via a linker moiety.The above linker moiety may be, but is not limited to, one or more selected from the group consisting of carbonate (-OC(O)O-), succinoyl, phosphate ester (-O-(O)POH-O-), sulfonate ester, amido (-C(O)NH-), amino (-NR-), carbonyl (-C(O)-), carbamate (-NHC(O)O-), urea (-NHC(O)NH-), disulfide (-SS-), ether (-O-), succinyl (-(O)CCH2CH2C(O)-), and succinamidyl (-NHC(O)CH2CH2C(O)NH-). The PEG-linked lipid may be ceramide, dimyristoylglycerol (DMG), succinoyl-diacylglycerol (s-DAG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylethanolamine (DSPE), or cholesterol. The PEG-lipid may comprise a linker moiety suitable for conjugating PEG to the lipid nanoparticle. Additionally, the helper lipid and / or cholesterol of the lipid nanoparticle may be used as the lipid constituting the PEG-lipid, but any lipid that can bind to PEG may be used without limitation. The lipid nanoparticle of the present invention may have a molar ratio, weight ratio, or volume ratio of the combination of the helper lipid, the cholesterol, and the PEG lipid component and the ionized lipid compound or its salt of 1:10 to 10:1, but is not limited thereto. In addition, the molar ratio, weight ratio, or volume ratio of the combination of the ionized lipid compound or its salt and the helper lipid, the cholesterol, and the PEG lipid component may be 1:10 to 10:1, or 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. The molar ratio, weight ratio, or volume ratio of the combination of the helper lipid, the cholesterol, and the PEG lipid component constituting the lipid nanoparticle of the present invention and the ionized lipid compound or its salt may be 1:1 to 4:1, preferably 1:1 or 4:1. The lipid nanoparticles of the present invention may comprise 5 to 20 mol % helper lipid, 20 to 60 mol % cholesterol, and 0.5 to 5 mol % PEG-lipid, or the lipid nanoparticles of the present invention may comprise 20 to 80 mol % of the above-mentioned ionizable lipid compound (e.g., the compound of formula (I) or (IV)) or a salt thereof, 0 to 20 mol % of the helper lipid, 20 to 65 mol % of the cholesterol, and 0 to 5 mol % of the PEG-lipid, wherein the helper lipid may be a phospholipid. Here, the mol % means a percentage obtained by dividing the number of moles of a specific component by the sum of the number of moles of all components. Composition In one aspect of the present invention, the present invention may be a composition comprising an ionic drug and (i) the ionizable lipid compound or salt thereof, or a composition comprising an ionic drug and (ii) the lipid nanoparticle. The ionic drug may be at least one selected from the group consisting of nucleic acid or nucleic acid-based drugs, peptides, protein drugs, protein-nucleic acid constructs, and ionic biopolymer-drug conjugates. The nucleic acid is an antisense oligonucleotide (ASO), short interfering RNA (siRNA), micro RNA (miRNA), self-amplifying RNA (SAM), circular RNA, messenger RNA (mRNA), crRNA, tracrRNA, single guide RNA (sgRNA), transfer RNA (tRNA), asymmetric interference RNA (aiRNA), antagomir, ribozyme, Dicer substrate RNA, short hairpin RNA (shRNA), plasmid DNA (pDNA), double stranded DNA (dsDNA), partial double stranded DNA, triple stranded DNA, partial triple stranded DNA, single strand It may be at least one selected from the group consisting of DNA (single stranded DNA, ssDNA), single stranded RNA (ssRNA), double stranded RNA (dsRNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), miRNA analogue or anti-miRNA, but is not limited thereto. The above ionic drug may be a therapeutic agent for treating a disease or a prophylactic agent for preventing a disease. The above composition can be used as a pharmaceutical composition for treating a disease. A composition comprising an ionic drug and (i) the ionizable lipid compound or salt thereof, or a composition comprising an ionic drug and (ii) the lipid nanoparticle, may exhibit a biologically equivalent or increased drug delivery effect compared to a composition comprising an ionic drug together with a conventionally known ionic lipid such as MC3. Additionally, a composition comprising an ionic drug and (i) the ionizable lipid compound or salt thereof, or a composition comprising an ionic drug and (ii) the lipid nanoparticle, may have a biologically equivalent or increased disease treatment or prevention effect or improved immunogenicity when compared to a composition comprising the same ionic drug together with a conventionally known lipid such as MC3. The composition may contain conventional non-toxic pharmaceutically acceptable additives. Examples of additives that can be used in the composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc., and examples thereof include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc. The composition of the present invention can be prepared in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration. When the composition of the present invention is formulated in an oral dosage form, additives such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, and diluents can be used. In addition, when the composition of the present invention is formulated in an injection form, water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc. can be used as additives. Hereinafter, the present invention will be described in detail with examples and the like to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. [Manufacturing Example] Manufacturing of ionized lipids The following manufacturing examples are merely illustrative of how the novel ionizable lipid compounds of the present invention can be manufactured, and are not intended to limit the scope of the present invention as defined in the appended claims. Manufacturing Example 1. Manufacturing of ionized lipid compounds 1 to 13 [Correction pursuant to Rule 91, December 2024] R: linear alkyl, branched alkyl or oxycarbonyl alkyl [Step 1] Synthesis of Compound B To a stirred solution of dichloromethane and diol (1.2 eq.), triethylamine (1.0 eq.) and 4-dimethylaminopyridine (0.1 eq.) were sequentially added, and compound A (1.0 eq.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (anhydrousNa2SO4), filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel (100 to 200 mesh) column chromatography to obtain compound B. [Step 2] Synthesis of Compound C Triethylamine (2.0 eq.) was added to a stirred solution of dichloromethane and compound B (1.0 eq.), and acryloyl chloride (1.2 eq.) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography to obtain compound C. [Step 3] Synthesis of compound F Potassium carbonate (K2CO3) (6 eq.) and compound E (2.5 eq) were added to a stirred solution of dimethylformamide and compound D (1.0 eq.) at room temperature. The mixture was stirred at 70°C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography to obtain compound F. [Step 4] Synthesis of compound G Hydrazine hydrate (2.0 eq.) was added to a stirred solution of methanol and compound F (1.0 eq.) at room temperature, and the mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to obtain compound G. [Step 5] Synthesis of ionized lipid compounds 1 to 13 A catalytic amount of hydroquinone (0.1 eq.) was added to a stirred mixture of compound G (1.0 eq.), acetonitrile, and compound C (4.0 eq.) at room temperature. The reaction mixture was heated to 70°C and stirred at 70°C for 48 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography to obtain ionizable lipid compounds 1-13. Manufacturing Example 2. Preparation of ionized lipid compound 14 R: linear alkyl, branched alkyl or oxycarbonyl alkyl [Correction pursuant to Rule 91, December 2024] [Step 1] Synthesis of Compound I To a stirred solution of dichloromethane and compound H (1.2 eq.) were added triethylamine (1.0 eq.) and 4-dimethylamoniopyridine (0.1 eq), and compound A (1.0 eq) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography to obtain compound I. [Step 2] Synthesis of Compound J Benzaldehyde (2.0 eq.) and molecular sieves were added to a stirred solution of ethanol and compound G (1.0 eq.), and the mixture was stirred at room temperature for 1 h. Then, sodium borohydride (NaBH4) (6 eq.) was added to the mixture at 0°C, and the mixture was stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The residue of the crude compound was quenched with dilute hydrochloric acid (aqueous HCl) and washed twice with dichloromethane. The separated aqueous layer was basified to pH 8 with a solution of NaHCO3, and extracted twice with 10% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound J. [Step 3] Synthesis of compound K Compound J (1.0 eq.) and hydroquinone in acetonitrile (0.1 eq.) were added to a stirred solution of compound I (2.2 eq.) at room temperature. The reaction mixture was heated to 70°C and stirred at 70°C for 72 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by NH-silica gel (100-200 mesh) column chromatography to obtain compound K. [Step 4] Synthesis of compound L To a stirred solution of methanol and compound K (1.0 eq.), ethyl acetate and palladium / carbon (Pd / C) (0.1 eq.) were added, and the mixture was stirred for 2 h under a hydrogen gas balloon pressure (60 psi) and room temperature. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain compound L. [Step 5] Synthesis of ionizable lipid compound 14 To a stirred solution of methanol and compound L (1.0 eq.), paraformaldehyde (10.0 eq.) and 1 drop of acetic acid were added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (NaCNBH3) (10.0 eq.) was added, and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was diluted with water and extracted twice with dichloromethane and 5% methanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by NH-silica gel (100-200 mesh) column chromatography to obtain ionizable lipid compound 14. Manufacturing Example 3. Preparation of ionized lipid compound 15 R: linear alkyl, branched alkyl or oxycarbonyl alkyl [Correction pursuant to Rule 91, December 2024] [Step 1] Synthesis of compound N Potassium carbonate (2.50 eq.) and compound E (1.30 eq.) were added to a stirred solution of dimethylformamide and compound M (1.0 eq.) at room temperature, and the mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound N. [Step 2] Synthesis of compound O 1,4-Dioxane-HCl (4M solution) was added to a stirred solution of dichloromethane and compound N (1.0 eq.) at room temperature, and the mixture was stirred for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound O. [Step 3] Synthesis of compound Q Potassium carbonate (2.50 eq.) and compound P (1.30 eq.) were added to a stirred solution of dimethylformamide and compound O (1.0 eq.) at room temperature, and the mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound Q. [Step 4] Synthesis of compound R Hydrazine hydrate (2.0 eq.) was added to a stirred solution of methanol and compound Q (1.0 eq.), and the mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to obtain compound R. [Step 5] Synthesis of compound S Compound C (2.50 eq.) and hydroquinone (0.1 eq.) dissolved in acetonitrile were added to a stirred solution of compound R (1.0 eq.) at room temperature. The mixture was heated to 70°C and stirred at 70°C for 72 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by NH-silica gel (100-200 mesh) column chromatography to obtain compound S. [Step 6] Synthesis of ionizable lipid compound 15 To a stirred solution of dichloromethane and compound S (1.0 eq.) was added 4 M 1,4-dioxane hydrochloric acid at 0°C, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with a NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative liquid chromatography (prep-HPLC) to obtain ionizable lipid compound 15. The structural formulas of the ionized lipid compounds 1 to 15 synthesized in the above manufacturing examples 1 to 3 are listed in Table 1 below. [Table 1] Meanwhile, the synthesized Lipid 1 to Lipid 15 were analyzed using either Bruker Ultrashield 400 or a spectrometer. 1HNMR spectra were measured. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in hertz (Hz), and the splitting pattern describes the diversity and is indicated using s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), or br (broad). Lipid 1 to Lipid 15 1 H NMR (400 MHz, CDCl3) data are shown in Table 2. [Table 2] [Experimental Example] Experimental Example 1. Characteristics of ionized lipids [Manufacture of lipid nanoparticles (LNPs)] For the production of LNP, cholesterol purchased from Sigma Aldrich (USA) was used, and DMG-PEG2000 (1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000) purchased from Avanti Polar Lipids (USA) was used as PEG lipid. In addition, DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and DSPC (1,2-Distearoyl-sn-glycero-3-PC) purchased from Avanti Polar Lipids (USA) were used as helper lipids. Lipids 1 to 5 and Lipids 8 to 15 synthesized in the above manufacturing examples were dissolved in ethanol together with the DOPE helper lipid, the cholesterol, and the PEG-lipid, respectively, and Lipids 1 to 4 and Lipids 8 to 15 synthesized in the above manufacturing examples were dissolved in ethanol together with the DSPC helper lipid, the cholesterol, and the PEG-lipid, respectively. When dissolved in ethanol, the mixing ratio of each substance is as described in Table 3. [Table 3] NanoAssemblr Ignite for LNP manufacturing TM (Precision Nanosystems, Inc., Canada) was used, and the total flow rate (TFR) was set to 12 mL / min. The ethanol in the LNPs prepared using Amicon Ultra Centrifugal Filter, MWCO 10 kDa (Millipore, USA) was removed, the buffer was exchanged, and then concentrated. During dilution, concentration, and exchange, the prepared LNPs were diluted with 1X DPBS to remove ethanol, and the LNPs were concentrated at the same time. [Method for analyzing physicochemical properties of LNP] The particle size, z-average diameter, and polydispersity index (PDI) were analyzed using a Zetasizer Pro (Malvern Instruments, United Kingdom). The "PDI" is a ratio that describes the homogeneity of the particle size distribution of the system. A PDI closer to 0 indicates monodispersity, and a PDI closer to 1 indicates polydispersity. [Method for measuring mRNA quantification and encapsulation efficiency (EE %)] mRNA content and EE% were measured using the Ribogreen RNA assay kit (Invitrogen, USA). Briefly, mRNA concentrations were measured for the manufactured mRNA / LNPs treated with Triton X-100 solution and untreated groups, and the ratio of mRNA encapsulated within LNPs among the total mRNA was calculated as EE%. The z-average diameter, PDI, and EE (%) measurements for each manufactured LNP are listed in Table 4 below, and the z-average diameter and EE (%) are plotted in Figures 1 and 2, respectively. [Table 4] As can be seen in Table 4 above, LNPs containing the original ionizable lipid compound were confirmed to have a narrow particle size distribution with a z-average diameter of less than 130 nm and a PDI of less than 0.12. Experimental Example 2. Nucleic Acid Delivery Efficacy of Novel Ionizable Lipid Compounds (in vitro) To confirm the nucleic acid delivery effect of the new ionizable lipid compound, a transfection efficiency test was conducted on HEK293T cells. HEK293T (human embryonic kidney-293T, ATCC) cell line was seeded at 15,000 cells / well in a 96-well microplate using DMEM media (supplemented with 10% Fetal Bovine Serum (FBS), Gibco), 1% penicillin-streptomycin) and incubated overnight (37°C, 5% CO2 incubator). As test LNPs to confirm the nucleic acid delivery efficacy, LNPs containing Lipid 1-(F1), Lipid 1-(F2), Lipid 9-(F1), Lipid 9-(F2), Lipid 11-(F1), Lipid 11-(F2), Lipid 12-(F1), Lipid 12-(F2), or Lipid 15-(F1) in Table 3 were used. Firefly luciferase mRNA (free mRNA) without LNP was used as a negative control, and LNPs containing MC3 (also referred to as DLin-MC3-DMA), an ionizable amino lipid (hereinafter referred to as MC3 LNP) were used as a positive control. Samples corresponding to 10 μL of test LNP per well and 25 ng of free mRNA were treated and incubated for 24 hours. 24 hours after transfection, Bright-Glo TM After treatment with the Luciferase Assay System (Promega, USA) solution, luciferase activity was measured. The average RLU measured for each LNP is described in Table 5 below, and each value is shown in Figure 3. [Table 5] As confirmed in Table 5 above, the mRNA delivery efficiency into cells was confirmed to increase by approximately 6,000 to 46,000 times when LNPs containing the present ionizable lipid compound were used compared to the mRNA delivery efficiency into cells when mRNA alone was used. In addition, the mRNA delivery efficiency into cells was confirmed to increase by approximately 10 to 80 times when LNPs containing the present ionizable lipid compound were used compared to when MC3 LNPs were used. Experimental Example 3. Nucleic Acid Delivery Efficacy of Novel Ionizable Lipid Compounds (in vivo) To evaluate drug delivery distribution and in vivo transfection efficiency after systemic administration of the manufactured material, intravenous and intramuscular injections were separately evaluated. Experimental Example 3.1. Nucleic Acid Delivery Efficacy Following Intravenous Administration of a Novel Ionizable Lipid Compound As a positive control, LNP containing MC3 (MC3:DSPC:Chol:DMG-PEG = 50:10:38.5:1.5) was used, PBS was used as a negative control, and as an experimental group material, LNP containing Lipid 8-(F2), Lipid 9-(F2), Lipid 10-(F2), Lipid 11-(F2), or Lipid 13-(F2) of Table 3 was used. LNPs corresponding to 0.5 mg / kg mRNA were injected intravenously into Balb / c mice (male, 5 weeks old) via tail vein. Six hours after injection, 150 mg / kg of D-Luciferin (Perkin Elmer, USA) was administered intraperitoneally, and 15 minutes later, the luminescence intensity (total flux) in the liver tissue of each mouse was quantitatively analyzed using an IVIS imaging system Luminar XR (Perkin Elmer, USA), thereby measuring the in vivo nucleic acid delivery efficacy of the novel ionizable lipid compound. The quantified luminescence intensities in the experimental and control groups are as described in Table 6. In addition, the relative luminescence intensities in the experimental and control groups and the presence or absence of luminescence expression according to nucleic acid delivery are shown in Figures 4 and 5, respectively. [Table 6] As confirmed in Table 6 above, the ionized lipid compound of the present invention showed superior in vivo mRNA delivery efficacy compared to the control group. Experimental Example 3.2. Nucleic Acid Delivery Efficacy Following Intramuscular Administration of a Novel Ionizable Lipid Compound As a positive control, LNP containing MC3 (MC3:DSPC:Chol:DMG-PEG = 50:10:38.5:1.5) was used, PBS was used as a negative control, and as an experimental group material, LNP containing Lipid 3-(F1), Lipid 3-(F2), Lipid 8-(F1), Lipid 8-(F2), Lipid 9-(F1), Lipid 9-(F2), Lipid 10-(F1), Lipid 10-(F2), Lipid 11-(F1), Lipid 11-(F2), Lipid 12-(F1), or Lipid 13-(F1) of Table 3 was used. Lipid nanoparticles corresponding to 0.25 mg / kg mRNA were administered intramuscularly to the thigh muscles of Balb / c mice (male, 5 weeks old). Control mice were also administered PBS into the thigh muscles. Six hours after injection, 150 mg / kg of D-Luciferin (Perkin Elmer, USA) was administered intraperitoneally, and 15 minutes later, the luminescence intensity (total flux) in the thigh muscle tissue of each mouse was quantitatively analyzed using an IVIS imaging system Luminar XR (Perkin Elmer, USA), thereby measuring the in vivo nucleic acid delivery efficacy of the novel ionizable lipid compound. The quantified luminescence intensities in the experimental and control groups are as described in Table 7. In addition, the relative luminescence intensities in the experimental and control groups and the presence or absence of luminescence expression according to nucleic acid delivery are shown in Figures 6 and 7, respectively. [Table 7] As confirmed in Table 7 above, LNPs containing the ionizable lipid compound of the present invention showed significantly increased in vivo mRNA delivery efficacy compared to the control group, regardless of the mixing ratio with lipid.

Claims

1. A compound represented by the following formula (I) or a salt thereof: L1-L2-L3-L4-L5 (I) The above L1 and L5 are each independently a group represented by the following formula (II), The above L2 is C 1-12 As linear alkyl, unsubstituted or substituted with a hydroxyl group, wherein L2 is C substituted with a hydroxyl group 1-12 If it is a linear alkyl, formula (I) does not include L1, The above L4 is C 1-12 It is a linear alkyl, The above L3 is a 6-membered heterocyclic amine or an aliphatic amine, and the 6-membered heterocyclic amine or aliphatic amine is C 1-6 Substituted with at least one selected from alkyl, amino group, 3-6 membered saturated or unsaturated carbocyclyl, 3-6 membered saturated or unsaturated carbocycloalkyl, 3-6 membered saturated or unsaturated heterocyclyl, and 3-6 membered saturated or unsaturated heterocycloalkyl, The above n is an integer of 0 or 1, The above X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, The above Rx′ is hydrogen, linear C1- 25 Alkyl, or branched C3- 25 It is alkyl, The above R1 and R2 are each independently linear C1- 30 Alkyl or branched C3- 50 As alkyl, they are the same or different from each other, The above R3 and R4 are each independently linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 As alkoxy, which are the same or different from each other, the linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 Alkoxy is unsubstituted or C 1-12 substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine, The above Rx″ is hydrogen, linear C1- 25 Alkyl, branched C3- 25 alkyl, 3-6 membered saturated or unsaturated carbocyclyl, 3-6 membered saturated or unsaturated carbocycloalkyl, 3-6 membered saturated or unsaturated heterocyclyl, or 3-6 membered saturated or unsaturated heterocycloalkyl, The above wavy lines indicate the bonding positions, The above heterocyclic amine is a cyclic amine group containing one or more heteroatoms selected from N, S or O, The above carbocyclyl is a cyclic group composed of carbon and hydrogen atoms, The above heterocyclyl is a cyclic group containing one or more heteroatoms selected from N, S or O, The above carbocycloalkyl is a carbocyclyl-linear C1-6 alkyl group or a carbocyclyl-branched C3-6 alkyl group, The above heterocycloalkyl is a heterocyclyl-linear C1-6 alkyl group or a heterocyclyl-branched C3-6 alkyl group.

2. In paragraph 1, A compound or a salt thereof, wherein the above L3 is a 6-membered heterocyclic amine.

3. In paragraph 1 or 2, A compound or a salt thereof, wherein the above L3 is a 6-membered heterocyclic amine containing two N atoms.

4. In any one of paragraphs 1 to 3, A compound or a salt thereof, wherein the above L3 has a diazabicyclo structure.

5. In any one of paragraphs 1 to 4, The above L2 is C 1-6 C substituted with linear alkyl or hydroxy groups 1-6 It is a linear alkyl The above L4 is C 1-6 Linear alkyl, compound or salt thereof.

6. In any one of paragraphs 1 to 5, The above X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, wherein the Rx′ is hydrogen or linear C1- 25 Alkyl, compound or salt thereof.

7. In any one of paragraphs 1 to 6, The above R1 and R2 are each independently linear C1- 30 As alkyl, compounds or salts thereof, identical or different from each other.

8. In any one of paragraphs 1 to 7, The above R1 and R2 are each independently linear C1- 12 Alkyl, compound or salt thereof. In any one of paragraphs 9 to 8, The above R3 and R4 are each independently linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, compounds or salts thereof, identical or different from each other.

10. In any one of paragraphs 1 to 9, The above L2 is C 1-4 C substituted with linear alkyl or hydroxy groups 1-4 It is a linear alkyl, The above L3 has a diazabicyclo structure, The above L4 is linear C 1-6 It is alkyl, The above X and Y are each independently -Rx′-C(=O)-O-, -Rx′-C(=O)-, -Rx′-NHC(=O)-, -C(=O)NH-Rx′-, -Rx′-O-, or -Rx′-NH-, The above Rx′ is hydrogen, or linear C1- 12 It is alkyl, The above R1 and R2 are each independently linear C2-8 alkyl and are the same or different from each other, The above R3 and R4 are each independently linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 As alkoxy, which are the same or different from each other, the linear C1- 20 Alkyl, linear C1- 20 Alkylene, branched C3- 40 Alkyl or C 4-30 Alkoxy is unsubstituted or C 1-12 A compound or a salt thereof, substituted with at least one selected from the group consisting of alkyl, Rx″-C(=O)-O-, Rx″-OC(=O)- or amine.

11. In any one of paragraphs 1 to 10, The above L1 and L5 are each independently a compound or a salt thereof represented by the following formula (III): The above R5 is linear C1- 30 It is alkyl, The above Z1 is -(Rx a ) k -O-, or (Rx a ) k -NH- and the above Rx a is linear C1- 25 alkyl, wherein k is an integer of 0 or 1, The above R6 is linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 As an alkoxy, the linear C1- 30 Alkyl, linear C1- 30 Alkylene, branched C3- 50 Alkyl or C 4-40 Alkoxy is unsubstituted or C 1-12 Alkyl, Rx b -C(=O)-O-, Rx b -OC(=O)- or is substituted with at least one selected from the group consisting of amines, The above Rx b is hydrogen, linear C1- 25 Alkyl, branched C3- 25 alkyl, 3-6 membered saturated or unsaturated carbocyclyl, 3-6 membered saturated or unsaturated carbocycloalkyl, 3-6 membered saturated or unsaturated heterocyclyl, or 3-6 membered saturated or unsaturated heterocycloalkyl, The above a is an integer of 1 or 2, The above carbocyclyl is a cyclic group composed of carbon and hydrogen atoms, The above heterocyclyl is a cyclic group containing one or more heteroatoms selected from N, S or O, The above carbocycloalkyl is a carbocyclyl-linear C1-6 alkyl group or a carbocyclyl-branched C3-6 alkyl group, The above heterocycloalkyl is a heterocyclyl-linear C1-6 alkyl group or a heterocyclyl-branched C3-6 alkyl group.

12. In paragraph 1, The compound is a compound or a salt thereof represented by the following formula (IV): The above L1, L2, X, Y, R3 and R4 are according to the definitions of L1, L2, X, Y, R3 and R4 described in paragraph 1, The above n1 and n2 are each integers from 0 to 12, The above n3 is an integer of 0 or 1.

13. A compound or a salt thereof, characterized in that the compound is selected from the group consisting of: (1)((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetranonanoate; (2) Tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (3) Tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (4) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetraheptanoate; (5) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(ethane-2,1-diyl)tetraheptanoate; (6) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl)) tetrakis(propanoyl))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetratridecanoate; (7) Tetrakis(2-ethylhexyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (8) Tetrakis(2-ethylhexyl) 6,6',6'',6'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrahexanoate; (9) Tetrakis(2-propylhexyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (10) Tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrabutyrate; (11) Tetrakis(2-ethylpentyl) 6,6',6'',6'''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrahexanoate; (12) Tetra((Z)-non-2-en-1-yl) 9,9',9'',9'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate; (13) (((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propanoyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl)octahexanoate; (14) di(henicosan-10-yl) 3,3'-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; and (15) ((3,3'-((3-(5-(3-hydroxypropyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl)azanediyl)bis(propanoyl))bis(oxy))bis(hexane-6,1-diyl)bis(2-hexyldecanoate.

14. A lipid nanoparticle comprising a compound or a salt thereof according to any one of claims 1 to 13, a helper lipid, cholesterol, and a PEG lipid.

15. In paragraph 14, The above helper lipids are dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylcholine (DSPC), palmitoyloleoylphosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, egg phosphatidylcholine (EPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), Dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylethanolamine (DSPE), phosphatidylethanolamine (PE), dipalmitoylphosphatidylethanolamine (DPPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-dioleoyl-sn-glycero-3-[phospho-L-serine] (DOPS), 1,2-dioctadecanoyl-sn-glycero-3-phosphoserine;A lipid nanoparticle, wherein the lipid nanoparticle is at least one phospholipid selected from the group consisting of DSPS, 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (DOPS), and sphingomyelin.

16. In paragraph 14 or 15, The above PEG lipid includes a lipid directly conjugated to PEG or linked to PEG via a linker moiety, The above linker moiety is at least one selected from the group consisting of carbonate (-OC(O)O-), succinoyl, phosphate ester (-O-(O)POH-O-), sulfonate ester, amido (-C(O)NH-), amino (-NR-), carbonyl (-C(O)-), carbamate (-NHC(O)O-), urea (-NHC(O)NH-), disulfide (-SS-), ether (-O-), succinyl (-(O)CCH2CH2C(O)-), and succinamidyl (-NHC(O)CH2CH2C(O)NH-), Lipid nanoparticles wherein the lipid linked to the PEG is ceramide, dimyristoylglycerol (DMG), succinoyl-diacylglycerol (s-DAG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylethanolamine (DSPE), or cholesterol.

17. In any one of paragraphs 14 to 16, A lipid nanoparticle comprising 20 to 80 mol% of the compound or its salt, 20 to 20 mol% of the helper lipid, 20 to 65 mol% of the cholesterol, and 0 to 5 mol% of the PEG lipid, wherein the helper lipid is a phospholipid.

18. Ionic drugs and (i) a compound or salt thereof according to any one of claims 1 to 13, or (ii) a lipid nanoparticle comprising a compound or a salt thereof of any one of claims 1 to 13, a helper lipid, cholesterol, and a PEG lipid; A composition comprising:

19. A composition according to claim 18, wherein the ionic drug is at least one selected from the group consisting of a nucleic acid or nucleic acid-based drug, a peptide, a protein drug, a protein-nucleic acid structure, and an ionic biopolymer-drug conjugate.

20. In claim 19, the nucleic acid is an antisense oligonucleotide (ASO), short interfering RNA (siRNA), micro RNA (miRNA), self-amplifying RNA (SAM), circular RNA, messenger RNA (mRNA), crRNA, tracrRNA, single guide RNA (sgRNA), transfer RNA (tRNA), asymmetric interference RNA (aiRNA), awntagomir, ribozyme, Dicer substrate RNA, short hairpin RNA (shRNA), plasmid DNA (pDNA), double stranded DNA (dsDNA), partial double stranded DNA, triple stranded DNA, or partial triple strand. A composition comprising at least one selected from the group consisting of DNA (Partial triple stranded DNA), single stranded DNA (ssDNA), single stranded RNA (ssRNA), double stranded RNA (dsRNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), miRNA analogue, or anti-miRNA.

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