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.

E12LA6B603（ILB3132，ILB-3132） is a novel ionizable amino lipid disclosed in patent WO2024198497A1, developed by MagicRNA, representing a highly efficient component for lipid nanoparticle (LNP) delivery systems.When formulated into LNPs, E12LA6B603 LNP achieves a remarkable 98.26% encapsulation efficiency for mRNA. It mediates superior in vitro transfection in dendritic cells (1.8E+05 intensity) and demonstrates best-in-class in vivo protein expression after intramuscular injection (2.2E+09 intensity). Most notably, in a B16-OVA melanoma model, therapeutic OVA-mRNA vaccines delivered by E12LA6B603 LNPs induced 100% complete tumor regression, highlighting its superior efficacy over benchmarks like DLin-MC3 and SM-102. Its biodegradable ester linkages and balanced structure make it a promising, potent candidate for next-generation mRNA vaccines and therapeutics.

C12-200 is a well-known cationic lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of therapeutic nucleic acids, including siRNA, mRNA, and CRISPR components. It is widely recognized for its high in vivo potency at low doses and is often used as a positive control ionizable lipid in research exploring new ionizable lipids.

SM86 is a cationic, ionizable lipid developed by Moderna as a core component of its lipid nanoparticle (LNP) platform for mRNA therapeutic delivery.SM-086 is structurally optimized and analogous to SM-102 (used in Moderna’s COVID-19 vaccines), with modifications aimed at enhancing mRNA delivery efficiency and safety.SM-86 serves as the primary cationic lipid in three investigational mRNA therapies targeting rare metabolic disorders:mRNA-3927: Restores propionyl-CoA carboxylase activity in propionic acidemia (PA). mRNA-3705: Delivers methylmalonyl-CoA mutase mRNA for methylmalonic acidemia (MMA). mRNA-3210: Provides phenylalanine hydroxylase mRNA to treat phenylketonuria (PKU).

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.

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 A9 is an ionizable cationic lipid (pKa = 6.27) that has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA and siRNA in vivo. LNPs containing lipid A9 and encapsulating non-stimulatory siRNA increase plasma levels of chemokine (C-C motif) ligand 2 (CCL2), indicating activation of the innate immune response, and decrease body weight in mice.

ATX-126(ATX-0126, 10p) is an ionizable cationic lipid (pKa = 6.38).It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of siRNA. Intravenous administration of LNPs containing ATX-126(ATX-0126, 10p) and encapsulating Factor VII siRNA decrease Factor VII blood levels in mice.

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.

SM-102 is an ionizable amino lipid that has been used in combination with other lipids in the formation of lipid nanoparticles.Administration of luciferase mRNA in SM-102-containing lipid nanoparticles induces hepatic luciferase expression in mice. Formulations containing SM-102 have been used in the development of lipid nanoparticles for delivery of mRNA-based vaccines.

ALC-0315 is an ionisable aminolipid that used for mRNA compaction and aids mRNA cellular delivery. ALC-0315 can be used to form lipid nanoparticle (LNP) delivery vehicles.

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.

ALC 0366 is an ionizable cationic lipid (pKa = 6.25) from Biontech,which is derived from ALC-0315. ALC0366 has been used as a key component of LNP to deliver BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors.

XH-04 (Lipid#4)​​ 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.

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.

LIPID168(pKa ~6.5) ​​ is an optimized ionizable lipid engineered for in vivo mRNA delivery to hematopoietic stem cells (HSCs) in bone marrow. Developed by ​​Yoltech Therapeutics​​ through high-throughput screening of lipid libraries, it features a ​​diethylamino head group​​ and a tailored hydrophobic tail structure that enables antibody-free targeting. When Lipid 168 was formulated into lipid nanoparticles (LNPs), it achieved ​​48.5% base editing efficiency​​ in bone marrow cells —surpassing benchmarks like LIPID-028 (19.7%)—and reduced off-target liver editing from 71% to 19% by incorporating ​​miR-122 target sequences​​. In humanized β-thalassemia models, LNP 168 delivered ABE8e mRNA/sgRNA to patient-derived HSCs, yielding ​​42.6% editing at the HBG promoter​​, reactivating fetal hemoglobin (γ-globin) and rescuing erythroid defects . Its bone marrow specificity is driven by a unique ​​protein corona​​ enriched in albumin, fibronectin, and fibrinogen . Safety studies confirmed transient immune responses and no cumulative toxicity . LIPID-168 represents a promising non-viral platform for curative gene therapies in blood disorders.

​​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.

A1-EP10-O18A​​ is an ​​asymmetric ionizable lipid​​ developed by Starna Therapeutics for mRNA vaccine delivery. Synthesized via Michael addition between amine alcohols and acrylates, its optimized structure—combining a hydrophilic C10 chain and hydrophobic unsaturated C18 tail—enables pH-dependent ionization. As the core component of the ​​STAR0225 lipid nanoparticle (LNP)​​ platform, it efficiently encapsulates mRNA and facilitates endosomal escape. Preclinical studies demonstrate superior in vivo mRNA delivery (vs. commercial SM102 LNPs), with enhanced local biodistribution and minimal off-target accumulation. This lipid underpins ​​STR-V003​​, an RSV prefusion F mRNA vaccine showing robust immunogenicity and protection in animal models, supporting its clinical transition (NCT06344975).

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.

E10i-494 is a branched ionizable lipid designed to enhance the delivery of mRNA and CRISPR-Cas9 ribonucleoprotein (RNP) complexes. It belongs to the Branched Endosomal Disruptor (BEND) lipid family, which features terminal branching to improve endosomal escape and cellular uptake.E10i-494 demonstrated exceptional performance in T cell engineering, achieving >80% transfection efficiency in primary human T cells. This is significantly higher than the ~70% efficiency achieved by the linear lipid C14-494.The isopropyl branch enhances the lipid's ability to penetrate and disrupt endosomal membranes, leading to improved release of mRNA and RNPs into the cytoplasm.Despite its high efficiency, E10i-494 exhibits low cytotoxicity, making it suitable for therapeutic applications.E10i-494 is particularly effective for delivering mRNA to T cells, making it a promising tool for CAR-T cell therapy and other immunotherapies.Its ability to deliver CRISPR-Cas9 RNPs efficiently also makes it suitable for in vivo gene editing applications.

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.​

Lipid S4 is an advanced ionizable lipid engineered for systemic mRNA delivery to the brain, leveraging SR-57227—a high-affinity 5-HT3 receptor ligand—as its core head group to enable targeted blood-brain barrier (BBB) penetration via receptor-mediated transcytosis, while incorporating amino linkers for pH-responsive ionization and biodegradable branched ester tails to facilitate efficient endosomal escape and intracellular mRNA release; optimized through orthogonal screening into OS4 LNP (formulated at S4/DOPE/Chol/DMG-PEG2k = 40:40:60:0.75 molar ratio), it demonstrated a 13.3-fold increase in brain mRNA expression compared to FDA-approved MC3 LNPs, and further conjugation with the Tat cell-penetrating peptide yielded OS4T LNP, boosting delivery efficiency by 12.7-fold over OS4 alone and enabling broad mRNA expression across neurons, astrocytes, microglia, and endothelial cells; validated in orthotopic glioblastoma models, OS4T delivered engineered IL-12 mRNA, suppressing tumor growth and extending median survival to 37 days (vs. 17 days for controls) with minimal systemic toxicity, positioning S4-based LNPs as a robust, translatable platform for CNS-targeted therapeutics.

IAJD-34 is a one-component ionizable amphiphilic Janus dendrimer specifically engineered for targeted mRNA delivery to the lung parenchyma, as described by Meshanni et al. in Nature Communications article "Targeted delivery of TGF-β mRNA to murine lung parenchyma using one-component ionizable amphiphilic Janus Dendrimers" . This synthetic nanoparticle self-assembles with mRNA through simple mixing in acetate buffer, forming stable dendrimersomes approximately 93-97 nm in size with high encapsulation efficiency (>95%) and a positive zeta potential (~48 mV). Its defining feature, highlighted in the study, is exceptional lung tropism after intravenous injection, enabling significantly higher luciferase expression in murine lungs compared to other organs. As demonstrated by Meshanni et al., IAJD 34 effectively delivers therapeutic mRNA (e.g., TGF-β mRNA) to the lower lung, inducing transient protein production with minimal systemic toxicity at appropriate doses (e.g., 10 µg), offering a promising strategy for treating parenchymal lung diseases.

304O13 is a novel Biodegradable lipidoid for RNA delivery.

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.

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-SCC-PH is a groundbreaking linker-degradable ionizable lipid (LDIL) that features a glutathione (GSH)-responsive cone-shaped molecular structure. This unique architecture enables superior endosomal escape and rapid mRNA release, making it highly effective for mRNA delivery. In vivo studies have highlighted its exceptional performance, showing a 176-fold increase in mRNA delivery efficiency to the liver compared to DLin-MC3-DMA, a widely used benchmark lipid. Both 4A3-SCC-PH and its structural analog, 4A3-SCC-10, also demonstrated significantly enhanced mRNA delivery efficacy compared to their non-disulfide-containing parent compounds and disulfide-containing controls with modified lipid tails.

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

Acuitas Lipid III-25 is an novel ionizable amine lipid used for mRNA delivery from Acuitas Therapeutics patent US 10,166,298 B2, with pKa 6.22, Liver Luc 1648 for 0.3mgkg(ng luc/g liver), Liver Luc 13880 for 1mgkg(ng luc/g liver) . It is an analgous of ALC-0315, showing higher activity than ALC-0315.