OF-C4-Deg-Lin is a novel ionizable lipid for RNA delivery.

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.

TS-202 is a novel ionizable lipid for RNA delivery.

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).

​​Lipid 10a-26​​ is an ionizable lipid developed by Orna Therapeutics for lipid nanoparticle (LNP) formulations. Lipid 10a-26 is a key ionizable lipid in the LNP-6 formulation. Through structural modification, it exhibits reduced binding to ApoE proteins and lowered liver affinity compared to traditional ionizable lipids. Instead, Lipid 10a-26 demonstrates strong splenic tropism—in non-human primate studies, it effectively delivers payloads to the spleen and immune cells in peripheral blood, such as T cells, NK cells, and macrophages, enabling the possibility of "in vivo CAR-T" therapy. Its pKa is tuned to approximately 6.0–6.5, allowing rapid protonation in the acidic endosomal environment, which promotes endosomal membrane disruption and efficient cytosolic release of circular RNA.

Fluorescent SM-102 (NBD-SM-102) is a premium, dye-conjugated ionizable cationic lipid designed for advanced nanomedicine and mRNA delivery research. By covalently integrating a bright, green-fluorescent nitrobenzofurazan (NBD) probe into the industry-standard SM-102 skeleton, this high-purity reagent operates as an indispensable visual tracer. It empowers researchers to seamlessly track cellular uptake, monitor tissue biodistribution, and quantify endosomal escape efficiencies via fluorescence microscopy and flow cytometry. Crucially, this NBD-SM-102 derivative preserves the native ionizable property (\(pK_a \approx 6.68\)) and optimal membrane-fusion dynamics required for lipid nanoparticle (LNP) assembly and transfection, ensuring experimental formulations accurately mimic functional delivery vectors. This reliable reagent is ideal for accelerating lipid-mix optimization, high-throughput screening, and nucleic acid therapeutics development pipeline.

GVS-18-B6 is a silicon ether-based ionizable lipid (pKa:6.15) developed by Genevant, optimized for mRNA-LNP delivery, characterized by a short-chain trialkyl structure with three C10 alkyl chains (including a cis double bond) and a dimethylamino (DMA) head group linked via a 4-carbon spacer (pKa ~6.15). Its LNP formulations exhibit a narrow particle size distribution (89 nm, PDI=0.06), high mRNA encapsulation efficiency (90%), and pH-dependent surface charge (−0.11 mV at pH 7.5 vs. +2.69 mV at pH 5.5), facilitating endosomal escape. ​​In vivo​​, GVS-18-B6 demonstrated superior liver-specific mRNA expression (5.30×10⁷ pg EGFP/g liver, 2.6× higher than MC3) with minimal spleen accumulation (liver/spleen ratio 92:1 vs. MC3’s 10:1), attributed to rapid non-enzymatic hydrolysis of its silicon ether bonds. This mechanism enables near-complete hepatic clearance within 6 hours in mice and 24 hours in NHPs, avoiding long-term organ retention (MC3 retained 25% in liver after 28 days). Compared to benchmarks (MC3, SM-102, LP-01), GVS-18-B6 showed enhanced potency in RBC hemolysis assays (pH 6.2), indicating earlier endosomal membrane disruption, and maintained stability through 12-month frozen storage or repeated freeze-thaw cycles. ​​Toxicity profiling​​ revealed minimal immunogenicity (MCP-1 levels 0.58×10⁶ vs. MC3’s 1.10×10⁶) and no ALT/AST elevation or anti-PEG antibody induction in NHPs after repeated dosing. Its species-agnostic clearance, low off-target effects, and high tolerability (6 mg/kg dose in mice) position GVS-18-B6 as a leading candidate for chronic disease therapies requiring frequent mRNA administration.

U-101 is an ionizable lipid for mRNA delivery. U101-LNP/IL-2F mRNA formulation demonstrats effective antitumor activity and safety.LNPs containing lipid U 101 and encapsulating mRNA encoding a fusion protein composed of IL-2, a linker, and CD25 inhibit tumor growth in an MC-38 mouse xenograft model.

93-O17O is a chalcogen-containing ionizable cationic lipidoid. It has been used in the generation of lipid nanoparticles (LNPs). LNPs containing 93-O17O localize to the spleen after intravenous injection into mice.LNPs containing 93-O17O have been used for the delivery of Cre recombinase and ribonucleoproteins for genome editing in mice and for the intratumoral delivery of cGAMP to enhance cross-presentation of tumor antigens.

Lipid B1​ is a next-generation ionizable lipid engineered for superior mRNA delivery, featuring a patented ​β-isobutylglutarate branching linker​ that optimizes nanoparticle assembly and intracellular release. Its unique structure combines a pH-responsive tertiary amine headgroup with twin C18 alkyl tails connected via biodegradable ester bonds, enabling precise control over lipid packing and endosomal escape. Preclinical studies demonstrate that Lipid B1-based LNPs (bLNPs) achieve ​**>75% transfection efficiency in vitro​ at ultra-low mRNA doses (1 μg), outperforming commercial benchmarks like SM-102. In vivo, subcutaneous administration of bLNPs delivers ​10-fold higher luciferase expression**​ than linear-chain analogs, with targeted biodistribution to lymph nodes and tumor sites. Clinically relevant data show 100% tumor prevention in prophylactic cancer vaccine models and 70% tumor regression in therapeutic settings when combined with checkpoint inhibitors. The ester-based backbone ensures rapid metabolic clearance, minimizing systemic toxicity risks (NOAEL >10 mg/kg in mice). Compatible with mRNA, siRNA, and CRISPR-Cas9 payloads, Lipid B1 is ideal for vaccines, gene therapies, and immuno-oncology. Its scalable 3-step synthesis (yield >80%) and lyophilization stability (-80°C, 12 months) make it a cost-effective solution for GMP-grade production. For advanced delivery with unmatched safety and efficacy, Lipid B1 sets a new standard in nucleic acid therapeutics.

NT1-O12B, an endogenous chemical and a neurotransmitter-derived lipidoid (NT-lipidoid), is an effective carrier for enhanced brain delivery of several blood-brain barrier (BBB)-impermeable cargos. Doping NT1-O12B into BBB-impermeable lipid nanoparticles (LNPs) gives the LNPs the ability to cross the BBB. NT-lipidoids formulation not only facilitate cargo crossing of the BBB, but also delivery of the cargo into neuronal cells for functional gene silencing or gene recombination.

NT1-O14B is a tryptamine-containing cationic lipidoid.1 It has been used in combination with other lipids in the formation of lipid nanoparticles (LNPs). Intravenous administration of LNPs containing NT1-O14B and encapsulating antisense nucleotides against tau decreases tau brain levels in mice.

Lipid C14-A1 is an ionizable lipid. C14-A1-LPN is a potent and safe LNP platform to deliver Foxp3 mRNA to CD4+ T cells to engineer immunosuppressive FP3T cells.

Lipid C12-A1 is an ionizable lipid. C12-A1-LPN is a potent and safe LNP platform to deliver Foxp3 mRNA to CD4+ T cells to engineer immunosuppressive FP3T cells. C12-A1 has a slightly lower average cell viability than C14-A1.

YSK 12C4 is an ionizable cationic lipid primarily used to enhance siRNA cellular delivery via multifunctional envelope-type nanodevices (MEND). YSK 12C4 promotes siRNA uptake and endosomal escape, effectively silencing genes in human immune cell lines.

C14-4 (C14-494,Lipid B-4,Lipid B4) is a novel ionizable lipid with the highest T-cell transfection efficiency and low cytotoxicity.The C14-4 ionizable lipid has been explored for CAR-T therapy.To screen the excellent formulations for mRNA delivery, a lipid library of 24 ionizable lipids was constructed to make iLNPs, which were used to deliver luciferase mRNA into Jurkat cells.[115] The optimal iLNPs formulation was C14-4 iLNPs (C14-4 ionizable lipid, DOPE, chol, and PEG at a molar ratio of 35%, 16%, 46.5%, and 2.5%) (Figure 6c). The optimal dose of luciferase mRNA for C14-4 iLNPs was 30 ng. Compared with electroporated CAR T cells, the CAR T cells engineered via C14-4 iLNPs showed potent cancer-killing activity when they were cocultured with Nalm-6 acute lymphoblastic leukemia cells. To obtain a safer and more effective CAR mRNA delivery vehicle, the orthogonal design provided 256 potential formulations, and 16 representative iLNPs formulations were evaluated.Through evaluating the safety, delivery efficiency, and transfection efficiency of 16 iLNPs, the formulation B10 (C14-4 ionizable lipid, DOPE, chol, PEG at a molar ratio of 40%, 30%, 25%, and 2.5%) was screened out as the optimal performing formulation. The luciferase expression based on B10 formulation was increased threefold than the initial formulation. Reducing the accumulation and clearance of iLNPs in the liver can increase the expression of CAR mRNA in T cells, further improving the therapeutic effect of CAR-T. Studies have shown that cholesterol analogs can alter the mechanisms of intracellular circulation and enhance the delivery of mRNA, which may be related to the reduced recognition of iLNPs by the Niemann Pick C1 (NPC1) enzyme.The addition of a hydroxyl group to various locations in the cholesterol molecule can alter the binding kinetics between the modified cholesterol and NPC1, and reduced NPC1 recognition of cholesterol. The results showed that replacement of 25% and 50% 7 α-hydroxycholesterol for cholesterol in iLNPs improved mRNA delivery to primary human T cells in vitro by 1.8-fold and twofold, respectively.C14-4 is one of the ionizable lipids to efficiently deliver mRNA to Jurkat cells or primary human T cells. It will effectively promote the development of mRNA delivery by iLNPs for CAR-T therapy.

PPZ-A10 is an ionizable cationic lipid.It has been used in the generation of lipid nanoparticles (LNPs) for the delivery of siRNA and mRNA in vitro and in vivo. Intraperitoneal administration of LNPs containing PPZ-A10 and encapsulating an mRNA reporter preferentially accumulates in hepatic Kupffer cells and splenic macrophages in mice.

Lipid 119-23 is an ionizable lipid for mRNA delivery. 119-23 LNP exhibits an enhanced capability to express functional mCre in several categories of immune cells, spanning the liver, spleen and lung.

Acuitas II-10 is an novel ionizable amine lipid used for mRNA delivery from Acuitas Therapeutics patent WO2016176330A1

Acuitas Lipid III-7 is an novel ionizable amine lipid used for mRNA delivery from Acuitas Therapeutics patent US 10,166,298 B2.

ND-O1 (SM-86 Analog-2) is a novel ionizable lipid designed to improve the delivery of siRNA via lipid nanoparticles (LNPs) for treating liver fibrosis. It is derived from SM-86 (structurally similar to SM-102, used in COVID-19 mRNA vaccines) but incorporates an ether bond within its hydrophobic tail, a first-of-its-kind modification aimed at enhancing delivery efficiency. In Vitro Efficiency: ND-O1 LNPs (LNP-O1) showed significantly higher siRNA transfection efficiency in activated fibroblasts compared to Lipid 5 LNPs (LNP-M). In Vivo Efficacy: In a CCl4-induced liver fibrosis mouse model, LNP-O1/siHSP47 (loaded with HSP47-targeting siRNA) reduced HSP47 expression by ~84%, threefold more effective than LNP-M. This led to a dramatic reduction in collagen deposition and marked improvement in liver fibrosis. Safety: The ether bond modification did not introduce additional toxicity, maintaining biocompatibility. ND-O1 represents a breakthrough in ionizable lipid design, demonstrating that strategic placement of ether bonds in hydrophobic tails can enhance LNP performance without compromising safety. Its success highlights its potential for clinical translation in RNA-based therapies for liver fibrosis and other hepatic diseases.

The LUMI-6 lipid, autonomously designed via the LUMI-lab platform, is a brominated ionizable lipid optimized for mRNA delivery. Formulated at a molar ratio of 35:28:34.5:2 (LUMI-6:DOTAP:cholesterol:C14-PEG2000), LNPs exhibit uniform physicochemical properties, including a hydrodynamic diameter of ~80 nm, polydispersity index (PDI) <0.2, and robust mRNA encapsulation efficiency. In vitro, LUMI-6 LNPs demonstrated 1.8-fold higher transfection potency in human bronchial epithelial cells compared to its debrominated counterpart (LUMI-6D), with minimal cytotoxicity confirmed by CCK-8 assays. In vivo, pulmonary delivery of CRISPR-Cas9 mRNA via LUMI-6 LNPs achieved ​20.3% gene editing efficiency in murine lung epithelial cells, surpassing SM-102 (Moderna’s clinical benchmark) and demonstrating ​preferential tropism for lung epithelium over endothelial cells—critical for inhaled therapies targeting cystic fibrosis and surfactant disorders. The brominated tail enhances endosomal escape through optimized protonation dynamics, though explicit pKa values remain unmeasured. Synthesized via high-throughput combinatorial chemistry and refined through AI-driven active learning, LUMI-6 combines scalable production with organ-selective delivery, positioning it as a transformative platform for pulmonary nucleic acid therapeutics.

Acuitas II-12 is an novel ionizable amine lipid used for mRNA delivery from Acuitas Therapeutics patent WO2016176330A1

Lipid 29 analogue-3 is an ionizable lipid designed for the delivery of RNA-based therapeutics, such as mRNA or siRNA.

L1 is a biodegradable, branched self-immolative lipid optimized for ​​high-efficiency mRNA delivery​​. Its disulfide-based architecture enables rapid glutathione-triggered degradation in the cytosol (liver half-life: 4.2 days), promoting rapid clearance while maintaining serum stability. In vivo, L1 achieves ​​exceptional mRNA translation​​, producing twice the hEPO protein levels of the clinically approved MC3 lipid at 0.1 mg/kg. Its apparent pKa (6.57) facilitates efficient endosomal escape without compromising safety: even at 5 mg/kg, L1 causes no significant body weight loss or sustained inflammation. Structural features (C7 alkyl tails, carbamate linker) balance potency and biodegradability, making L1 ideal for mRNA vaccines and protein-replacement therapies.

80-O18 is a lipidoid known for its exceptional ability to enhance overall cellular uptake, showcasing significant potential as an effective delivery agent.

Acuitas Lipid III-2 is an ionizable amine lipid with two identical ester tails adjacent to C6 position relative to amine from patent:WO2017075531A1 with the similar activity as ALC-0315. The head of lipid is propanolamine which can effectively encapsulate mRNA used in gene therapies which depends on the availability of a safe and efficient delivery vehicle.

RCB-4-8​​ is a biodegradable ionizable lipid nanoparticle (LNP) engineered for efficient pulmonary mRNA delivery and in vivo genome editing, as detailed in the primary research article ​​"Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing"​​ (Li et al., Nature Biotechnology 2023）. Synthesized from a combinatorial library of 720 biodegradable lipids via a three-component reaction system, RCB-4-8 features an alkyne-containing lipid tail and tertiary amine headgroup, optimized through high-throughput screening for superior lung-targeting capabilities. Its unique molecular design incorporates hydrolyzable ester and carbonate groups, enabling rapid biodegradation (<30% lung retention at 48 h vs. >90% for conventional lipids) while maintaining high transfection efficiency. When formulated with DOTAP instead of DOPE, RCB-4-8 LNPs achieved ​​100-fold higher luciferase mRNA expression​​ in murine lungs compared to FDA-approved MC3 LNPs and mediated ​​95% GFP knockout​​ in vitro. In Ai9 reporter mice, intratracheal delivery of RCB-4-8 loaded with Cre mRNA edited ​​53% of total lung cells​​ after three doses, while codelivery with Cas9 mRNA/sgRNA yielded ​​7.2% tdTomato⁺ cells​​, rising to ​​17%​​ when combined with AAV-sgRNAs. With an optimal particle size of ​​85.7 nm​​ (PDI 0.11) and ​​>87% mRNA encapsulation​​, RCB-4-8 supports repeat dosing and represents a transformative platform for inhalable gene therapies targeting congenital lung diseases like cystic fibrosis.

D-Lin-MC4-DMA(MC4) is a cationic lipid that has been synthesized for Lipid nanoparticles (LNPs) to deliver the siRNA.