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.

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.

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.

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).

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).

306-O12B is a cationic lipidoid.306-O12B LNP is more efficient than MC-3 LNP in inducing loss-of-function mutations in Angptl3 through CRISPR-Cas9-based genome editing. It has been used in the generation of lipid nanoparticles (LNPs). Intravenous administration of LNPs containing 306-O12B and encapsulating an mRNA reporter accumulate specifically in the mouse liver. LNPs containing 306-O12B and encapsulating mRNA encoding the Cas9 nuclease (mCas9) and single-guide RNA targeting Angptl3 (sgAngptl3), the gene encoding angiopoietin-related protein 3, have been used to induce CRISPR-mediated gene knockdown in mice resulting in a reduction of serum Angptl3 protein, LDL, and triglyceride levels. A novel ionizable lipids library was constructed by a combinatory solvent-free Michael addition reaction between disulfide bondincorporated acrylate lipid tails and amine-containing heads. In this library, the tail-branched bioreducible ionizable lipid 306-O12B was screened out. Due to the presence of special ester bonds and branches in lipid tails, the accumulation of iLNPs in the liver was increased, and endosome escape was prompted. These iLNPs were used to deliver CRISPR-Cas9 mRNA and sgRNA targeting to angiopoietin-like 3 (Angptl3). Compared with FDA-approved MC3, 306-O12B induced more specific and efficient Angptl3 gene knockout in the liver, resulting in significant decrease in the levels of serum Angptl3 protein, low-density lipoprotein cholesterol (LDL-C), and triglyceride. According to the molecular shape hypothesis outlined several decades ago, the increase of branches can create ionizable lipids with more cone-shaped structure to enhance the destructiveness of the membrane structure of the endosome and increase mRNA release. However, it is unknown whether the structural stability of iLNPs will be sacrificed with the increase of branches. The optimal branches and chain length need to be further explored.

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.

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.

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.

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.

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.

D-Lin-MC2-DMA(MC2) is a cationic lipid that has been synthesized for Lipid nanoparticles (LNPs) to deliver the siRNA.

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

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.

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.

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.

4A3-SCC-10 is a disulfide bond-containing biodegradable ionizable cationic lipid (pKa = 6.22) that has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA in vitro and in vivo. LNPs containing 4A3-SCC-10 and encapsulating a Cy5-RNA reporter have improved endosomal escape ability over Cy5-RNA-encapsulated LNPs containing 4A3-SC-10, which does not contain disulfide bonds, in HeLa cells. Intravenous administration of LNPs containing 4A3-SCC-10 and encapsulating an mRNA luciferase reporter selectively accumulate in mouse liver.

A fluorescent molecule-conjugated SM-102 derivative for tracking and locating the position of SM-102.

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

​​C-a16​​ is an ionizable lipid engineered through Mannich reaction chemistry, designed to revolutionize mRNA delivery by synergizing high efficiency with minimized immune activation. Synthesized by reacting a phenolic tail derivative, formaldehyde, and a branched tertiary amine core under optimized ethanol conditions, this lipid integrates antioxidant phenol groups directly into its structure. These phenol moieties serve as intrinsic radical scavengers, effectively neutralizing intracellular reactive oxygen species that typically degrade mRNA and trigger inflammation.In lipid nanoparticle formulations, C-a16 constitutes the functional backbone, enabling superior mRNA encapsulation efficiency while maintaining a stable nanoparticle size of approximately 80–100 nm. Critically, it outperforms conventional lipids like DLin-MC3-DMA by achieving significantly higher target-protein expression in vivo alongside markedly reduced pro-inflammatory cytokine secretion. The antioxidant capability is not incidental but fundamental—quenching the phenol groups drastically diminishes both ROS suppression and delivery efficacy, confirming the design's mechanistic elegance.C-a16 represents a paradigm shift: its biomimetic antioxidant architecture addresses the chronic trade-off between delivery potency and immunogenicity, unlocking safer therapeutic applications for vaccines and gene therapies.

Lipid VII is a novel ionizable cationic lipid developed by Sanofi.Lipid VII demonstrates exceptional performance as a lipid nanoparticle delivery system, combining high efficiency with outstanding safety. Cellular assays reveal VII achieves 180,000 RLU transfection efficiency under serum conditions, surpassing traditional SS-OP systems by 2.25-fold while maintaining perfect 100% cellular viability and eliminating cytotoxicity risks that plague alternatives. In vivo systemic delivery shows rapid whole-body biodistribution, reaching photon emission levels exceeding 1.00E+10 photons/sec within 48 hours. VII exhibits superior organ targeting with a liver-specific accumulation ratio of 9.0, outperforming SS-OP systems by 50%, while reducing off-target spleen accumulation by 20%. Its versatility is further validated in therapeutic protein expression, where structural analogs achieve erythropoietin concentrations of 14 ng/mL, exceeding industry standards by 180%. For vaccine applications, VII generates a median HAI titer of 7,611 against H1N1 influenza—540 times higher than baseline buffers and more than double the next-best formulation. This evidence establishes VII as a breakthrough technology, offering unmatched efficiency, precision targeting, and clinical-grade safety across diverse applications.

SM-86 Analog-1 is a novel ionizable lipid designed to improve the delivery of RNA via lipid nanoparticles (LNPs) It is derived from SM-86,with 8 carbon within its hydrophobic tail.

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.

GVS-18-B6 is a silicon ether-based ionizable lipid 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.

ADA (Acid-Degradable Anionic Lipids) is revolutionizing mRNA delivery with its unique azido-acetal linker, enabling rapid hydrolysis in endosomes (pH ~6.0). This breakthrough technology ensures efficient endosomal escape, significantly enhancing mRNA delivery to target cells. ADA-LNPs excel in delivering mRNA to the spleen and liver, making them ideal for immune-related therapies.By degrading into biocompatible byproducts, ADA minimizes long-term tissue persistence and toxicity.ADA-LNPs outperform traditional LNPs, delivering mRNA more effectively to immune cells like macrophages and B cells.