Moderna Lipid 26（Lipid M） is an ionizable cationic lipid (pKa = 6.75) that has been used in the generation of lipid nanoparticles (LNPs) for mRNA delivery in vivo. LNPs containing lipid M and encapsulating mRNA encoding influenza virus genes increase anti-influenza virus IgG titers in cynomolgus monkeys without inducing local edema, erythema, or systemic levels of IL-6.

4A3-SC8 is a novel Ionizable amino lipid for RNA delivery.The CRISPR-Cas9 gene editing system has been a hotspot in the field of gene therapy, especially the gene correction induced by homology-directed repair (HDR). However, its application has various obstacles, such as large molecular weight, poor stability, off-target risk, and the complexity of codeliver multiple genes. Farbiak et al. established a novel ionizable lipid library consisting of four distinct amine cores (3A3, 3A5, 4A1, 4A3) and nine peripheries with different alkyl chain lengths (SC5-SC14), and screened out a class of iLNPs with ability of encapsulating Cas9 mRNA, sgRNA and donor DNA simultaneously. The delivery efficiency (quantified by luciferase mRNA expression) and iLNPs toxicity were evaluated with three different cell lines (HEK293T, HeLa, and IGROV-1), indicating the formulation containing 4A3-SC8 was the best. 4A3-SC8 iLNPs successfully induced HDR in HEK293 cells by one-pot delivery of Cas9 mRNA, sgRNA, and the correct ssDNA template. Confocal microscopy imaging showed that a portion of blue fluorescence in cells was corrected to green fluorescence. Furthermore, the nucleic acid ratios of Cas9: sgRNA: donor DNA loading in iLNPs at a ratio of 2:1:3 could maximize the HDR efficiency with the editing efficiency up to 23%, which breaks through the current bottleneck of HDR efficiency of only 1–5%. This progress is undoubtedly an important advance in the gene therapy field to cure diseases caused by genetic mutations.

CICL1 (L829)​​ is a ​​novel ionizable cationic lipid​​ specifically engineered for ​​targeted lipid nanoparticles (tLNPs)​​ that enables efficient in vivo delivery of mRNA payloads to ​​CD8+ T cells​​. Designed to overcome limitations of conventional LNPs, CICL-1 (L-829)​​significantly ​​reduces off-target delivery to the liver​​ and exhibits ​​rapid clearance​​ compared to benchmark lipids like ALC-0315, while demonstrating ​​enhanced biodegradability and tolerability​​ in rodent and primate models. When incorporated into CD8-targeted tLNPs, CICL 1 (L829 enables ​​preferential transfection of CD8+ T cells​​ over other immune subsets, facilitating the generation of functional ​​anti-CD19 or anti-CD20 CAR T cells directly *in vivo​​*. These tLNP-engineered CAR T cells mediate ​​rapid, deep B-cell depletion​​ in humanized mice and cynomolgus monkeys, with repopulating B cells exhibiting a naïve phenotype suggestive of immune reset. By eliminating the need for ex vivo manufacturing or lymphodepleting chemotherapy, the L829-tLNP platform represents a ​​safer, scalable approach​​ for accessible CAR T therapy in oncology and autoimmune diseases.

Lipid 854 is an ionizable cationic lipid that has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA in vivo. Lipid 854 has been optimized based on Lipid 88.

Lipid 29 analogue-2 is an ionizable lipid designed for the delivery of RNA-based therapeutics, such as mRNA or siRNA.

Genevant CL1 (lipid 10) is a novel ionizable lipid for rna delivery.Lipid 10 rapidly accumulated in the liver within the first hour of dosing (reflecting LNP uptake), but levels then steadily declined over the ensuing 2 weeks period, similar to MC3.Lipid 10 afforded more than double the expression of either approved lipid. We also observed high splenic expression for ALC-0315, which correlated with higher MCP-1 levels.Animals received a single 5 µg IM dose of LNP encapsulating firefly luciferase (fLuc) mRNA. Whole body imaging was performed 6 h later and expression at the injection site quantified. Lipid 10, ALC-0315, and SM-102 showed similar expression at the injection site, all greater than the older generation benchmarks lipids (DLinDMA, KC2, MC3). Lipid 10 and ALC-0315 also showed high expression in the liver, while SM-102 was less, and more similar to MC3.Lipid 10-based LNP reported similar anti-HA IgG titers to MC3 and ALC-0315 (Comirnaty) LNP, and higher than the SM-102 (SpikeVax) LNP composition. MCP-1 levels were generally similar, although the ALC-0315 composition had a significantly higher response at the 5 µg dose. All formulations reported good stability when stored frozen at −80 °C or at 2–8 °C for 1 month.

Lipid 2,2(8,8) 4C CH3 is an ionizable cationic lipid (pKa = 6.69).1 It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of siRNA in vivo. LNPs containing lipid 2,2(8,8) 4C CH3 and encapsulating siRNA targeting Factor VII decrease plasma Factor VII protein levels by 90% in mice.

​​DM3-BTA-14​​ is a cationic lipid compound engineered for high-efficiency mRNA delivery developed by Hefei AlphaNA Biotechnology. Its structure features a rigid benzene-1,3,5-tricarboxamide core linked to a protonatable dimethylamino headgroup (-N(CH₃)₂) via a propylene spacer (-CH₂CH₂CH₂-) and two saturated C14 alkyl chains. This design enables ≈90% endosomal escape efficiency , superior lymph node targeting for vaccines , and effective tumor-specific mRNA delivery . It outperforms benchmark lipids while maintaining low cytotoxicity, forming stable nanoparticles with cholesterol/DSPC/DSPE-PEG (50:39:10:1 ratio) for therapeutic applications.

DMA4-H228 is a novel, biodegradable lipidoid specifically engineered for spleen-targeted mRNA delivery.​​ Its structure combines a dimethylamino (DMA4) headgroup with a unique hyperbranched lipid tail (H228) synthesized via Michael addition, incorporating ester bonds for enhanced biodegradability. This design enables the formation of stable lipid nanoparticles (LNPs) (~170 nm) with high mRNA encapsulation efficiency (>96%). Critically, DMA4-H228 exhibits exceptional intrinsic tropism for the spleen (>98% targeting efficiency after IV administration), requiring no external targeting ligands. It selectively delivers mRNA to splenic antigen-presenting cells (APCs), including dendritic cells, macrophages, and B cells. This triggers potent immune activation: rapid IFNα secretion, upregulation of APC maturation markers (CD86/CD40), and robust antigen-specific immune responses. Demonstrating significant therapeutic potential, DMA4-H228-based mRNA vaccines effectively inhibit tumor growth in melanoma models (e.g., B16F10-OVA). This correlates with increased tumor-infiltrating CD8⁺ T cells, a shift towards pro-inflammatory M1 macrophages, elevated antigen-specific antibodies (IgG), and strong T cell responses (evidenced by IFNγ⁺ spots). Its ability to bypass liver tropism and directly activate splenic APCs makes DMA4-H228 a powerful platform for next-generation mRNA vaccines and cancer immunotherapy.

CICL 207 is structurally optimized based on Lipid CICL-1. CICL207​​ is a constrained ionizable cationic lipid designed for lipid nanoparticle (LNP) delivery systems developed by Capstan. Its structure features a ​​rigid cyclic backbone​​ (e.g., pyrrolidine-derived core) paired with a ​​tertiary amine group​​ that ionizes at acidic pH (pKa ~6.5–7.0), enhancing endosomal escape. The lipid includes ​​asymmetric hydrophobic tails​​ (likely C14–C18 alkyl/ester chains) to stabilize LNP membranes and improve nucleic acid encapsulation. Integrated into LNPs (e.g., 58% CICL-207, 10% DSPC, 30.5% cholesterol, PEG-lipids), it enables targeted delivery to T cells (anti-CD5/CD8 tLNPs) with ​​high transfection efficiency​​ (spleen T cells >70% mCherry+), ​​reduced liver uptake​​, and ​​low toxicity​​ (no significant ALT/AST elevation in rats). Its constrained design balances stability, tissue specificity, and biocompatibility for gene therapy applications.CICL 207 (F50) significantly outperforms CICL-1 by delivering dramatically enhanced target cell transfection with reduced off-target effects. It achieves >50% transfection efficiency in splenic T-cells—nearly double that of CICL-1—while slashing off-target expression in liver cells to <5% (versus >15% for CICL-1. This precision translates to superior therapeutic outcomes: CICL-207 enables ~95% B-cell depletion in CAR-T applications, far exceeding CICL-1 ’s ~60% efficacy. Critically, it maintains an exceptional safety profile, showing no significant liver toxicity or inflammatory cytokine elevation even at high doses. Furthermore, CICL-207 demonstrates 2-fold higher transfection efficiency in hematopoietic stem cells, enabling robust gene editing. Its optimized pKa (~6.5) and constrained amine structure enhance endosomal escape while minimizing Kupffer cell uptake, making it ideal for targeted therapeutics requiring both potency and safety.​

Si5-N14 is a lipid-based molecule engineered with siloxane groups, designed specifically for efficient mRNA delivery to the lungs. The incorporation of siloxane units boosts the cellular uptake of mRNA-loaded lipid nanoparticles (LNPs) and enhances their ability to escape from endosomes. These properties significantly increase the overall effectiveness of mRNA delivery, making Si5-N14 a promising tool for targeted therapeutic applications.

514O6,10 is an ionizable lipidoid. 514O6,10 formulated LNPs facilitate mRNA delivery to the pancreas.

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.

503O13 is a next-generation, biodegradable lipid nanoparticle (LNP) engineered for highly efficient and targeted siRNA delivery. Designed through rational structure-activity criteria—including optimal tail length (O13), tertiary amines, and a surface pKa ≥5.5—this single-component LNP achieves unparalleled gene silencing with an ultra-low EC50 of 0.01 mg/kg in preclinical models.503O13 outperforms non-degradable counterparts (e.g., C12-200) with improved toxicity profiles—no hepatic necrosis or pancreatic inflammation—while maintaining rapid blood clearance (t1/2: 6 min) and organ-specific accumulation (liver/spleen).

L-369 (Lipid 369,L369) is novel class of ionizable lipid for siRNA delivery with improved in vivo elimination profile with excellent translation across species,including NHP, wide safety margin.

TNT-b10 is a novel Lipid-like compound suitable for delivery of siRNA and mRNA both in vitro and in vivo TNT-b10 LLNs was more than 10-fold more potent than TNT-a10 LLNs formulated under the same condition.

Lipid 331 is a biodegradable cyclic ionizable lipid. LNPs containing Lipid 331 result in robust transfection in the nasal and lung tissues of mice and efficient transfection of lung epithelial cells and lung-resident APCs. Lipid 331 is a promising candidate for mRNA vaccine delivery, offering the potential for further enhancing the potency of mRNA vaccines.

Lipid A6 is an ionizable cationic and biodegradable alkyne lipid (pKa = 6.65).It has been used with other lipids in the formation of lipid nanoparticles (LNPs) for the delivery of mRNA. LNPs containing lipid A6 and encapsulating mRNA encoding human erythropoietin (EPO) increase and then maintain homeostatic levels of hemoglobin in the blood in an adenine-induced mouse model of renal anemia.

LIPID 14 is a novel ionizable lipid used for mRNA delivery.In 2021, Elia et al. used lipid 2 LNPs and lipid 14 LNPs to deliver mRNA encoding SARSCoV-2 human Fc-conjugated receptor binding domain (RBDhFc mRNA). While both lipid 274 LNP RBD-hFc mRNA and lipid 14 LNP RBD-hFc mRNA induced equal cellular and humoral responses in mice at an mRNA dose of 5 μg, only lipid 14 LNP RBD-hFc mRNA exhibited strong immunogenicity following intradermal administration. Both intradermal administration and intramuscular administration of lipid 14 LNPs could activate antigen presenting cells (APCs), thus inducing cellular responses.

A12-Iso5-2DC18 is a novel amine containing lipid can be used for mRNA delivery, activate the stimulator of interferon genes (STING) pathway, and exhibit anti-tumor immunity.

A18-Iso5-2DC18 that could not only deliver mRNA vaccines robustly but also activate the stimulator of interferon genes (STING) pathway. A18-Iso5-2DC18 strongly binds to the stimulator of interferon genes (STING) and induces potent cytolytic T lymphocyte responses, resulting in substantial antitumor immunity (Miao et al. 2019).

113-O16B is a disulfide bond-containing ionizable cationic lipidoid. It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA.

80-O16B is a disulfide bond-containing ionizable cationic lipidoid. It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of CRISPR complementary single-guide RNA (sgRNA) and Cas9 for genome editing in mice. LNPs containing 80-O16B conjugated to phenylboronic acid (PBA) and encapsulating an mRNA reporter increase luciferase reporter expression in HeLa cancer cells.2 LNPs containing 80-O16B conjugated to PBA and encapsulating p53 mRNA decrease the viability of DU145 prostate and SiHa and HeLa cervical cancer cells.

306-O12B-3 is an ionizable lipidoid with cationic properties, commonly used in lipid nanoparticle (LNP) formulations for antisense oligonucleotide (ASO) delivery. When administered intravenously in mice, LNPs incorporating 306-O12B-3 exhibit liver-specific accumulation. Studies show that ASO-loaded LNPs containing 306-O12B-3 effectively silence hepatic PCSK9 expression by targeting the proprotein convertase subtilisin/kexin type 9 gene. Additionally, when combined with the cationic lipidoid NT1-O14B (Item No. 37095), these LNPs can deliver tau-targeting ASOs to the brain, reducing tau protein levels in mice.

AA3-DLin is an ionizable cationic amino lipid (pKa = 5.8) that has been used in combination with other lipids in the formation of lipid nanoparticles (LNPs) for the delivery of mRNA.LNPs containing AA3-DLin and encapsulating mRNA for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein induce immunogenicity in mice.

ALC-0315 analogous-1 is a derivative of the ionizable cationic amino lipid ALC-0315. It has been used in the synthesis of ionizable cationic lipids used in the generation of lipid nanoparticles (LNPs).

ALC-0315 analgous-3 is an butanolamine ionizable lipid with both ester bonds located adjacent to C8 relative to the amine head. The introduction of ester linkages can improve the clearance of the lipid in the liver. This compound is analgous to ALC-0315.

Lipid 15 is an ionizable amino lipid used for the generation of Lipid nanoparticles .

An analog of SM-102. The ethanolamine amino lipid head enhances encapsulation of mRNA. The lipid has primary esters at C7 position relative to the amine nitrogen. The primary lipid tail has 8 carbon tail. The lipid can be used for mRNA-based therapies which depends on the availability of a safe and efficient delivery vehicle.

ALC-0315 analogue-2 is an analogue of ALC-0315. ALC-0315 is an ionisable aminolipid that is responsible for mRNA compaction and aids mRNA cellular delivery and its cytoplasmic release through suspected endosomal destabilization. ALC-0315 can be used to form lipid nanoparticle (LNP) delivery vehicles. Lipid-Nanoparticles have been used in the research of mRNA COVID-19 vaccine.