CL15F 9-5, a piperidine-based ionizable lipid, exhibits favorable properties for mRNA delivery in lipid nanoparticles (LNPs). Its apparent pKa ranges between 6.24–7.15, ideal for mRNA encapsulation and endosomal escape. LNPs formulated with CL15F 9-5 (50:38.5:10:1.5 molar ratio of ionizable lipid:cholesterol:DSPC:DMG-PEG2k) demonstrated high mRNA encapsulation efficiency (>90%) and maintained physicochemical stability (size, PDI, zeta potential) during storage at 4°C for 5 months . In vitro, CL15F 9-5 LNPs showed superior luciferase expression in HEK-293T cells compared to CL4F-based LNPs. In vivo, liver-targeted LNPs delivered hEPO mRNA effectively, with sustained serum hEPO levels post-storage. Intravenous administration of FLuc mRNA-loaded CL15F 9-5 LNPs yielded strong hepatic bioluminescence, confirming liver tropism. As a vaccine candidate, CL15F 9-5 induced robust antigen-specific cellular immunity in mice, with a 14-fold increase in IFN-γ spots compared to SM-102. Its enhanced stability is attributed to reduced aldehyde impurities, minimizing mRNA-lipid adduct formation.

TG4C is an ionizable cationic lipid (pKa 6.71) optimized for mRNA delivery via lipid nanoparticles (LNPs). When formulated into LNPs carrying human EPO mRNA, it significantly elevates serum EPO levels in mice. Furthermore, aerosolized TG4C-based LNPs containing HGF mRNA demonstrate therapeutic potential in pulmonary emphysema models, showing reduced inflammatory cytokines (IL-1β, IL-6, TNF-α) in bronchoalveolar lavage fluid after elastase-induced lung injury.

XH-04 ​​is an ionizable lipid engineered for advanced mRNA delivery developed by ​​JiaChen West Lake Biotech. Its core structure features a central benzene ring with asymmetric hydrophobic tails (C9-C10 chains) and pH-responsive tertiary amines that enable efficient mRNA encapsulation and endosomal escape. As detailed in CN113993839A, XH04 outperforms industry benchmarks (e.g., MC3 lipid), boosting protein expression by ​​>10-fold​​ in BHK cells. In PCT/CN2024/121624, JiaChen further demonstrated its utility in lung-targeted LNPs (tLNP/tLCNP). When combined with cationic lipids (e.g., DOTMA at 2:1 molar ratio), XH 04 redirects >80% of mRNA delivery to murine lungs—overcoming liver tropism—while maintaining low toxicity. The lipid’s benzenic core and optimized alkyl chain geometry (patent claims 1-9) are credited for enhanced endosomal disruption and mRNA release kinetics. JiaChen’s innovations position XH-04 as a cornerstone for next-generation mRNA therapeutics.

DLin-KC2-DMA is a highly potent ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of siRNA. It represents a significant advancement over earlier generations of lipids, such as DLin-DMA, due to its dramatically improved gene silencing efficiency.

YSK 05 is a pH-sensitive cationic lipid. YSK 05 improves the intracellular trafficking of non-viral vectors. YSK 05-MEND shows significantly good gene silencing activity and hemolytic activity. YSK 05 overcomes the suppression of endosomal escape by PEGylation. YSK 05 effectively enhances siRNA delivery both in vitro and in vivo.

DODMA, also known as MBN 305A is a a cationic lipid containing the unsaturated long-chain (18:1) oleic acid inserted at both the sn-1 and sn-2 positions. It has been used in the composition of lipospomes formulated as stable nucleic acid lipid particles that can encapsulate siRNA or other small molecules to be used for drug delivery

9322-O16B is a lipidoid for the efficient delivery of antiCD19 mRNA CAR to murine primary macrophages. LNP 9322-O16B is more efficient than delivery with lipofectamine 2000 (LPF2K) or MC3.

93-O17S is an imidazole-based synthetic lipidoid for in vivo mRNA delivery. Lipid nanoparticles (LNPs) with 93-O17S promotes both the cross-presentation of tumor antigens and the intracellular delivery of cGAMP (STING agonist).

IC8 is an ionizable cationic lipid. It has been used in combination with other lipids for the formation of lipid nanoparticles (LNPs). Immunization with severe acute respiratory coronavirus 2 (SARS-CoV-2) spike glycoprotein mRNA in IC8- and manganese-containing LNPs induces IgG responses to SARS-CoV-2 Delta and Omicron variants in mice.1 Administration of mRNA encoding B7-H3 X CD3 bispecific T cell engaging (BiTE) antibodies in IC8-containing LNPs reduces tumor growth in MV4-11 and A375 mouse xenograft models.

LP-01 is an ionizable cationic amino lipid (pKa = ~6.1). It has been used in the generation of lipid nanoparticles (LNPs). LNPs containing LP-01 and encapsulating both Cas9 mRNA and modified single-guide RNA (sgRNA) for the transport protein transthyretin (Ttr) induce gene editing in liver cells in mice in a dose-dependent manner resulting in reduced serum Ttr levels for at least 12 months.

ssPalmO-Phe(SS-OP) is a self-degradable material for the delivery of oligonucleotides. ssPalmO-Phe is a self-degradable derivative of ssPalm that is self-degraded in the intraparticle space by a specific hydrolytic reaction. ssPalmO-Phe is beneficial for overcoming the plasma/endosomal membrane, LNP-ssPalmO-Phe can be used to deliver both nucleic acids.

5A2-SC8 is a dendrimer for miRNA delivery to late-stage liver tumors with low hepatotoxicity. 5A2-SC8 shows potent EC50 < 0.02 mg/kg (siRNA against FVII (siFVII)) in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors. 5A2-SC8 is a degradable lipid-like compound (ester-based dendrimer) for small RNAs delivery.5A2-SC8, was obtained by screening a large library of more than 1500 ester-based dendrimers containing ionizable amino groups, which have three tertiary amine heads and five lipid tails. Based on this library, the in vitro transfection efficiency of different formulations of 5A2-SC8 iLNPs was evaluated, discovering the optimal formulation (5A2-SC8, DOPE, cholesterol, PEG at a molar ratio of 15:15:30:3) of 5A2-SC8 iLNPs for delivering fumarylacetoacetate hydrolase (FAH) mRNA to liver.After the intravenous injection via tail, the model mice of hepatorenal tyrosinemia type I had strong FAH protein expression, which prevented body weight loss and increased the survival rate of hepatorenal tyrosinemia mice . In addition to introducing utility of 5A2-SC8 iLNPs for the therapeutic intervention, the 5A2-SC8 iLNPs containing DOTAP have been used to establish complex mouse models via intravenous injection, including in situ liverspecific cancer model and in situ lung-specific cancer model. Based on this iLNPs delivery system, 5A2-SC8 induced model construction method overcomes the time-consuming and costly disadvantages of traditional animal models establishing methods, including transgenesis and gene engineering in embryonic stem cells.

4A3-SC7​​ is a proprietary, ionizable lipid component central to the SORT LNP platform developed for targeted organ delivery. It features a unique ​​branched-tail structure​​ designed to enhance mRNA encapsulation and endosomal escape. In the study, it served as the ​​primary ionizable lipid​​ in both Liver SORT LNPs and updated Lung SORT LNPs. For liver targeting, it was formulated at ​​15.04 mol%​​ alongside helper lipids (DOPE: 23.04%, Cholesterol: 38.72%), PEG-lipid (DMG-PEG2000: 3.2%), and the liver-targeting lipid ​​4A3-Cit (20 mol%)​​. This specific composition (Total lipid:RNA = 20:1 wt/wt) yielded LNPs with ​​~74 nm size​​, ​​low PDI (0.17)​​, and ​​high encapsulation efficiency (87%)​​ for large mRNAs like ABE editors (~5000 nt). Its branched-tail architecture was critical for stabilizing nanoparticles encapsulating large RNAs, overcoming a key limitation of previous formulations. 4A3-SC7-based Liver SORT LNPs enabled ​​>40% base editing in hepatocytes​​ in vivo, achieving durable correction of the disease-causing SERPINA1 mutation in PiZ mice and significantly reducing pathological protein aggregates. In the updated DualSORT system, 4A3-SC7 was also paired with ​​DORI​​ (instead of DOTAP) for improved lung targeting, demonstrating its versatility as a foundational ionizable lipid for multi-organ gene editing therapeutics.

FTT5 is a lipid-like compound for efficient delivery of long mRNAs in vivo.

D-Lin-MC3-DMA(MC3) is the most potent cationic lipid that has been synthesized for Lipid nanoparticles (LNPs) to deliver the siRNA.

CKK-E12 is a ionizable lipid in combination with other lipids make up the lipid nanoparticles which are used to deliver RNA-based therapeutics. cKK-E12 was highly selective toward liver parenchymal cell in vivo.Multitail lipids usually have three or more tails and tend to form more cone-shaped structures due to the increase of tail crosssection, which enhances the endosome escape and mRNA delivery efficiency.CKK-E12 is an ionizable lipid with four lipid tails and diketopiperazine core-based head. It has shown excellent efficiency in delivering CRISPR-Cas9 mRNA and sgRNA.cKK-E12 iLNPs encapsulated mRNA was used to investigate the effect of Toll-like receptor 4 (TLR4) on iLNPsmediated mRNA delivery, and it has been demonstrated that the targeting, safety and efficacy of iLNPs are closely related to disease state. In other words, even though iLNP delivers therapeutic mRNA to a given cell type in one disease state, it is not guaranteed to deliver mRNA to the same cell type in another disease. As same as MC3 and C12-200, CKK-E12 is also used to be a positive control ionizable lipid when exploiting new ionizable lipids.

Lipid 8 iLNPs were used to deliver CRISPR-Cas9 mRNA and sgRNA which targeted to the PLK1 gene. The safety and excellent intracerebral diffusion performance of lipid 8 iLNPs ensured that the survival of murine glioblastoma multiforme (GBM) mice was extended. The median survival was extended by approximately 50% and the overall survival was increased by 30%. The treatment of metastatic adenocarcinoma was executed by the EGFRtargeted lipid 8 iLNPs. These iLNPs possessed the ability of tumor targeting, which could increase the accumulation of CRISPR-Cas9 mRNA and sgRNA within the tumor cells. After a single intraperitoneal administration,
80% PLK1 gene was edited and the overall survival of mice with high-grade ovarian cancer malignant ascites was enhanced by
80% . These results demonstrate the clinical potential of CRISPR-Cas9 gene editing system can be delivered by iLNPs for treating tumors, and provide new ideas for tumor gene therapy.

ALC 0307 is an ionizable amino lipid developed by Acuitas Therapeutics, serving as the critical functional component in lipid nanoparticles (LNPs) for targeted therapeutic delivery. As the core cationic lipid in specific LNP formulations (e.g., k-abe for CPS1-Q335X correction), its key feature is pH-dependent chargeability: it remains neutral at physiological pH but becomes positively charged in acidic environments like endosomes. This property enables efficient encapsulation of nucleic acid payloads (>97% efficiency, e.g., base editor mRNA/gRNA complexes) and facilitates endosomal escape via membrane disruption post-cellular uptake.​​ Its optimized structure promotes selective hepatocyte targeting by binding endogenous apolipoprotein E (ApoE), which subsequently interacts with LDL receptors on liver cells. Preclinical studies show rapid clearance (>99.5% plasma reduction in 14 days) and manageable transient toxicity (mild, reversible cytoplasmic vacuolation in hepatocytes, short-term ALT/AST elevation). LNPs containing ALC0307, alongside helper lipids (cholesterol, DSPC, and PEG-lipid ALC-0159), form stable ~73 nm particles with low polydispersity. This combination enables repeatable, liver-directed delivery of gene editing therapeutics with minimized off-target effects, underpinning its use in individualized in vivo gene correction therapies.

L319 (LIPID 319) is a novel ionizable, biodegradable lipid for delivery of short interfering RNAs (siRNAs). L319-LPN displays rapid elimination with pKa of 6.38 and also shows well tolerated up to 10 mg/kg.

EDMPC, a cationic lipid, has an enhanced ability to deliver DNA to pulmonary tissues. EDMPC mediates intralobar DNA delivery to rodents.

Lipid C3 is an ionizable cationic lipid (pKa = 5.05-5.671).1,2 It has been used in the formation of lipid nanoparticles (LNPs) for the delivery of mRNA in vitro and in vivo.

Iso-A11B5C1 is an ionizable lipid. The iso-A11B5C1 LNP demonstrates a high level of muscle-specific mRNA delivery efficiency. exhibiting transfection efficiency comparable to the commercially available lipid SM-102, while considerably reducing inadvertent mRNA expression in main organs such as the liver and spleen.Additionally, study results show that intramuscular administration of mRNA formulated with iso-A11B5C1 LNP caused potent cellular immune responses, even with limited expression observed in lymph nodes.

TCL053 is an ionizable amino lipid.1 It has been used in the generation of lipid nanoparticles (LNPs) and has a pKa value of 6.8. LNPs containing TCL053 and encapsulating mRNA encoding the Cas9 nuclease, in combination with LNPs containing TCL053 and encapsulating single-guide RNA (sgRNA) targeting the Rosa26 locus, have been used to induce CRISPR-mediated gene editing in the mouse gastrocnemius muscle.TCL053 is an ionizable lipid that has received FDA approval for preparing mRNA vaccines. It is a three-tailed ionizable lipid to overcome the disadvantage of nonrepeatable administration of AAV vectors. In addition, combined with limb perfusion administration, TCL053 iLNPs could transiently deliver CRISPR-Cas9 mRNA and sgRNA to multiple muscle tissues, reducing immunogenicity and increasing the safety of iLNPs. It is great progress for treating Duchenne muscular dystrophy and other diseases that require multiple doses.

Lipid 10 is a novel ionizable cationic lipid be used for delivery of therapeutic RNA to the Bone Marrow in Multiple Myeloma Using CD38-Targeted with Lipid 10-LNP.

98N12-5 is an ionizable cationic lipid. It has been used in combination with other lipids in the generation of lipid nanoparticles (LNPs). LNPs containing 98N12-5 and encapsulating proprotein convertase subtilisin kexin type 9 (PCSK9) siRNA selectively accumulate in the liver and reduce total serum cholesterol levels in mice and rats and serum LDL levels in cynomolgus monkeys.

Lipid 2298 is a novel ionizable lipid developed by Sai Biomedicine demonstrates excellent performance with a spleen-to-liver ratio of 3.448​ and a very high total expression level of 2.4E+07. Lipid 2298 offers a strong balance of efficient systemic protein production and clear preferential delivery to the spleen.

CL15F 7-5 is a piperidine-based ionizable lipid from the CL15F library, characterized by a symmetrically branched tail structure with a 7-carbon main chain and a 5-carbon side chain. This moderate tail length positions it between short-tail (e.g., CL15F 6-4) and long-tail (e.g., CL15F 14-12) variants, granting it a unique balance in mRNA delivery properties. Its LNPs exhibit optimized organ selectivity, enabling significant mRNA expression in both the spleen and muscle, as demonstrated by in vivo luciferase assays following intravenous and intramuscular administration. This lipid structure facilitates a favorable DSPC surface density on LNPs, which moderates interactions with serum proteins like ApoE, thereby reducing rapid hepatic clearance and promoting extrahepatic delivery. In vaccine applications, CL15F 7-5 LNPs encapsulating SARS-CoV-2 RBD mRNA elicited robust anti-RBD IgG titers and neutralizing antibodies in mice, outperforming the clinically benchmarked SM-102 lipid. The piperidine headgroup further contributes to storage stability by minimizing the generation of aldehyde impurities that can form mRNA-lipid adducts. Consequently, CL15F 7-5 represents a versatile lipid for developing stable, spleen-targeted mRNA vaccines and therapeutics, leveraging tail-length engineering for enhanced efficacy without complex formulation changes.

BHD-C2C2-PipZ, as an efficient ionizable cationic lipid, achieves high encapsulation efficiency and controllable release of mRNA through its unique chemical structure. In PEG-free 3P-LNPs, its electrostatic interaction with tripolyphosphate successfully replaces the steric stabilization effect of traditional PEG, offering a new strategy to circumvent PEG immunogenicity. Its hepatic distribution pattern further indicates that LNP design should take into account the heterogeneity of the organ microenvironment.

Lipid A-12 is an ionizable cationic lipid from Capstan Therapeutics and a close analog of CICL-1 (L829). The structure was modified by the extension of the headgroup linker from a two-carbon (C2) to a three-carbon (C3) spacer compared to CICL-1 (L829).

4A3-LNSC8​ is a strategically designed thiourea-functionalized ionizable lipid that serves as the foundational core for a novel anion-coordination delivery platform. Its structure features a central 4A3 amine headgroup symmetrically extended with four hydrophobic tails, each incorporating a biodegradable ester linkage and a key thiourea-bridged linker. The inclusion of the thiourea group is the pivotal innovation, as it provides specific hydrogen-bonding sites capable of interacting with various halide anions (F⁻, Cl⁻, I⁻). When formulated into lipid nanoparticles (LNPs) without anion coordination, 4A3-LNSC8 itself exhibits a characteristic liver tropism, efficiently delivering mRNA to hepatocytes following systemic administration, with a measured surface pKa of approximately 5.54. However, its primary significance lies in its role as a versatile precursor. The strong anion-binding capability of its thiourea linkers allows for predictable modulation of the LNP's properties. Upon binding with anions like Cl⁻, the resulting complex (e.g., Cl-4A3-LNSC8) undergoes a significant pKa shift, which reprograms the LNP's in vivo fate, redirecting mRNA delivery from the liver to secondary lymphoid organs such as the spleen and lymph nodes. Thus, 4A3-LNSC8 is not merely an efficient ionizable lipid but a programmable scaffold that enables precise control over organ-targeting specificity through simple anion coordination, offering a powerful rational design strategy for advanced mRNA therapeutics.