PyCB lipid (MeDZ) is a rationally designed zwitterionic ionizable lipid that serves as a core functional component in the novel three-component (ThrCo) lipid nanoparticle (LNP) platform. It is synthesized by covalently attaching a zwitterionic PyCB structure to the hydroxyl group of the clinically available ionizable lipid ALC-0315.Its key feature is its pH-responsive behavior. At physiological pH (~7.4), the PyCB headgroup exhibits zwitterionic properties, forming charge-assisted hydrogen bonds with water molecules (PyCB-H₂O complexes). This confers high hydrophilicity to the LNP surface, enhancing stability in aqueous environments and reducing nonspecific protein adsorption in the bloodstream. This zwitterionic surface effectively mimics and replaces PEGylated lipids, thereby avoiding PEG immunogenicity and the associated Accelerated Blood Clearance (ABC) effect upon repeated administrations.Crucially, in the acidic environment of endosomes (pH ~6.5), the PyCB group undergoes strong protonation, rapidly transforming into a cationic state (PyCB-H₃O⁺ complexes). This promotes efficient fusion with and disruption of the endosomal membrane, facilitating the escape and cytoplasmic release of encapsulated mRNA.By replacing both cholesterol and PEGylated lipids in traditional LNPs, PyCB lipid enables the redirection of LNP biodistribution from the liver to the spleen, achieving superior spleen-specific mRNA translation and enhancing antigen presentation for potent immune activation.

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).

DLin-DMA is an ionizable amino lipid with cationic properties and a pKa of 6.7. It is widely utilized in lipid nanoparticle (LNP) formulations alongside helper lipids to enable efficient nucleic acid delivery.

AMG-1541 is a degradable cyclic amino alcohol ionizable lipid optimized for mRNA vaccine delivery using lipid nanoparticles (LNPs). Formulated typically with DOPE, cholesterol, and PEG-lipids, AMG 1541 LNPs have a diameter of ~85 nm, PDI of 0.107, and encapsulation efficiency of 67%, ensuring stability and efficient mRNA delivery. In vitro, it outperforms benchmarks like SM-102, showing enhanced transfection in cells such as C2C12 and PBMCs. In vivo, intramuscular administration in mice results in robust protein expression within 6 hours and induces potent immune responses, including high antibody titers and Th1-biased T-cell activation, with minimal inflammation. Mechanistically, its β-hydroxyl groups form hydrogen bonds with mRNA phosphate backbones, facilitating endosomal escape. AMG1541 degrades rapidly under enzymatic conditions, reducing long-term toxicity, and is effective for vaccines targeting pathogens like influenza and SARS-CoV-2, making it a promising candidate for clinical applications.

CF3-2N6-UC18​​ is a rationally designed chloroquine-inspired ionizable lipid that enables robust mRNA delivery and genome editing. It integrates three modular components: a 7-trifluoromethyl-substituted quinoline scaffold (mimicking chloroquine’s endosomolytic properties), a hexamethylenediamine linker with two ionizable nitrogen atoms (pH-responsive protonation), and two unsaturated oleyl (C18:1) hydrophobic tails (enhancing membrane fusion and nanoparticle stability). This lipid self-assembles into ecoLNPs (endosomolytic chloroquine-like lipid nanoparticles) with spherical morphology (~200 nm diameter, 98% mRNA encapsulation). Its pH-sensitive activity triggers endosomal escape through dual mechanisms: ​​proton sponge effect​​ (buffering endo-lysosomal pH) and ​​saposin B-mediated membrane disruption​​ (molecular docking confirms chloroquine-like binding to lysosomal saposin B). In vitro, ecoLNPs outperform commercial reagents (18.9-fold higher mRNA delivery than Lipofectamine 2000) and penetrate 3D cell models. They resist serum/RNase degradation and retain >90% activity after 7-day storage at 4°C. In vivo, ecoLNPs achieve tissue-specific mRNA expression via multiple routes (intravenous, intramuscular, etc.), with strong lymph node tropism (90.2% after intramuscular injection) comparable to SM-102 LNPs (Moderna’s COVID-19 vaccine carrier). They mediate efficient Cre mRNA-driven recombination and CRISPR-Cas9 editing in transgenic mice. CF3-2N6-UC18’s modular design, stability, and dual endosomal escape strategies position it as a versatile platform for mRNA vaccines, gene therapy, and genome editing applications.

6Ac1-C12 is an ionizable cationic lipid with a hexaester degradable core and six C12 hydrophobic alkyl tails, featuring a pKa around 6.0 and strong endosomal escape capacity. Its four-component LNPs deliver mRNA mainly to liver endothelial cells after IV injection and remain stable for 30 days at 4°C. Formulated without cholesterol, its three-component system enables lung-targeted delivery with low in vivo toxicity, and the ester core facilitates biodegradation for versatile mRNA applications.

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.

MK-16(pKa 6.86) is a specialized lipid designed to traverse the blood-brain barrier (BBB) for effective mRNA delivery. Its formulation, MK 16 BLNP, leverages dual mechanisms involving caveolae and γ-secretase to facilitate BBB penetration, ensuring the targeted and efficient transport of functional mRNA to diverse brain cell types. Demonstrating excellent tolerability across a range of dosing regimens, MK16 BLNP represents a promising platform for brain-targeted therapeutic applications.

AA-T3A-C12 is a leading anisamide-tethered lipidoid (AA-lipidoid) identified through a combinatorial library screening for targeted RNA delivery to activated fibroblasts, offering a promising approach to treat liver fibrosis.AA-T3A-C12 is a leading anisamide-tethered lipidoid (AA-lipidoid) identified through a combinatorial library screening for targeted RNA delivery to activated fibroblasts, offering a promising approach to treat liver fibrosis. It is synthesized via a one-pot, two-step modular method that combines anisamide—a ligand for sigma receptors overexpressed on activated hepatic stellate cells (HSCs)—with a T3A polyamine core and C12 epoxide tails, enabling efficient siRNA encapsulation in lipid nanoparticles (LNPs). In vitro, AA-T3A-C12 LNPs exhibit enhanced cellular uptake and gene silencing in activated fibroblasts, dependent on sigma receptor binding, as confirmed by haloperidol blockade studies, and outperform non-targeted analogs and the FDA-approved MC3 LNPs in fibroblast selectivity.In a mouse model of CCl4-induced liver fibrosis, AA-T3A-C12/siHSP47 LNP achieves approximately 65% knockdown of heat shock protein 47 (HSP47), a key fibrotic target, leading to significant reduction in collagen deposition and fibrosis alleviation, with a good safety profile and no exacerbation of liver injury.

Si12-C10 is a siloxane-incorporated lipid for spleen-targeting mRNA delivery. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy.

AO12 is a novel antioxidant ionizable lipid derived from SM-102 skeleton with para-hydroxyphenyl propionic acid side chains. Integrated into LNPs, it efficiently scavenges diverse reactive oxygen species including ·OH and ONOO⁻, shielding encapsulated mRNA from oxidative degradation. It retains fine LNP formulation features and cellular uptake capacity of conventional lipids, boosting in vivo mRNA translation. Applied for regenerative mRNA therapy and CRISPR gene editing against fibrosis and inflammatory disorders.

A10 (Compound 16) is a diketopiperazine‑based ionizable lipid disclosed in WO 2025/217298 A1 (PCT/US2025/023899) developed by NAVA Therapeutics that enables potent, cell‑selective in vivo delivery of mRNA and nucleic acids without targeting ligands. It forms stable, well‑tolerated lipid nanoparticles (LNPs) that preferentially transfect hematopoietic stem cells (HSCs), bone marrow progenitors, lung epithelium, endothelium, and immune cells while minimizing liver off‑target delivery. In both mice and non‑human primates, A10‑containing LNPs drive functional mRNA expression and gene editing in CD34⁺ HSCs at clinically relevant low doses (0.25–1.0 mg/kg), supporting in vivo HSC gene therapy without ex vivo manipulation.

SM-102 azide is an azide-modified derivative of the clinically validated SM-102 ionizable lipid. Designed specifically for advanced Lipid Nanoparticle (LNP) formulation, this product integrates a reactive azide (-N₃) group to enable effortless, high-yield functionalization via click chemistry. It is the ideal tool for researchers and developers looking to construct targeted nucleic acid delivery systems, build diverse lipid libraries, or track LNPs in vivo.

A5-CE-C7-6 is an ionizable lipid engineered for spleen-targeted mRNA delivery, integrating a hydroxylated dual-amine core (A5) for enhanced mRNA binding and endosomal escape, a biodegradable carbonate ester linker (CE) enabling rapid hydrolysis (61% degradation in 24 h), and branched heptyl hydrophobic tails (C7-6) that optimize nanoparticle stability and spleen tropism.​​ When formulated into cholesterol-free lipid nanoparticles (B-8 formulation), its unique architecture—combining hydroxyl groups for cellular uptake, carbonate-mediated biodegradability, and branched-chain fluidity—achieves unprecedented efficiency: low pKa (~6.0) minimizes liver accumulation while enabling ​​21% transfection of splenic NK cells​​, outperforming benchmark systems like MC3 SORT LNPs by >10-fold in spleen-specific delivery and establishing a new standard for in vivo immune cell engineering.

Ionizable lipid-3( SM-102 analogu) is a cationic lipid for nucleic acid delivery, with the ability to form lipid nanoparticle mRNA vaccines that exhibit in vitro stability and immunostimulatory activity.This SM-102 analogue retains the ionizable tertiary amine and asymmetric hydrophobic architecture while replacing the ester linkages with carbonate groups and repositioning the hydroxyl functionality. These modifications are designed to tune biodegradability, membrane interactions, and LNP delivery performance.

CA2d is an ionizable lipid developed for systemic mRNA delivery to the central nervous system. Its architecture combines an MK-0752-derived CNS-accessing moiety, a short three-carbon diamine spacer, a tertiary ionizable amine, and two acetal-containing hydrophobic tails. When formulated with DOPE, cholesterol and DMG-PEG2000, CA2d LNPs crossed the blood-brain barrier through caveolae- and γ-secretase-associated transcytosis and delivered mRNA to neurons, astrocytes, microglia and brain endothelial cells. Following intravenous administration of FLuc mRNA at 0.5 mg/kg in mice, CA2d produced 16.6-fold higher brain expression than MC3 and 8.6-fold higher expression than SM-102 at 6 hours. CA2d was further evaluated in repeated brain-cell transfection studies, a pilot rhesus macaque experiment and a tPA-modified TGF-β1 mRNA formulation for ischemic stroke. These results support CA2d as a promising preclinical research lipid for investigating non-viral CNS mRNA delivery; it has not been clinically validated.

CSL3 is a pH-switchable cationic lipid optimized for siRNA LNP delivery. Its core design features central pyridine and two ortho-methoxy groups, forming intramolecular hydrogen bonds under endosomal pH 5–6 to trigger conformational flip, which drives membrane fusion and efficient endosomal escape—an advantage absent in control lipid CSL4 without methoxy moieties. Formulated with DSPC, cholesterol and DMG-PEG2000 at a fixed molar ratio, CSL3-based LNPs achieve 85–95% siRNA encapsulation, uniform particle size and decent serum stability. In vitro tests show potent gene silencing with low cytotoxicity; in vivo intravenous administration enables obvious liver accumulation and dose-dependent Factor VII knockdown in mice, proving its great potential for hepatic RNAi therapeutic research.

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.

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.

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.

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.

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.

A3B7C2 is an imidazole‑based ionizable lipid, featuring dimethylamino‑imidazole head group connected via ester‑type degradable C2‑linker to two C14 unsaturated aliphatic tails. It forms LNPs achieving 98 % splenic transfection proportion, potent for splenic dendritic cell‑targeted mRNA delivery, superior to MC3, SM102.

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.​

A1B7C2 is an imidazole‑based ionizable lipid from the IMIL library. It features dimethylamino‑propyl imidazole head group, paired with B7 hydrophobic tails and C2 degradable ester linkers. LNPs assembled from A1B7C2 can effectively accumulate within the spleen after systemic administration. It mediates mRNA expression in splenic tissue, and is applied as a key control compound to investigate structure‑activity relationships for spleen‑targeted nucleic acid delivery.

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.

EB-Lipid is an innovatively engineered ionizable lipid designed to replace conventional PEG-lipid in mRNA vaccine formulations. Its structure comprises three key components: an Evans Blue-derived headgroup with high affinity for albumin, a tetraethylene glycol linker that enhances colloidal stability, and dual oleate tails for anchoring into lipid bilayers. This molecular design enables EB-Lipid to actively recruit endogenous albumin, forming an albumin-rich protein corona on the surface of lipid nanoparticles (LNPs). Following intramuscular administration, these albumin-bound EB-LNPs are preferentially transported through lymphatic vessels rather than entering the bloodstream, thereby avoiding hepatic accumulation and associated hepatotoxicity risks.Experimental data demonstrate that EB-LNPs achieve significantly higher accumulation in lymph nodes, where they are efficiently internalized by dendritic cells via albumin receptor-mediated endocytosis (e.g., gp60). This process enhances antigen presentation and activates robust cellular and humoral immune responses. In both tumor models (B16-OVA and HPV-associated) and infectious disease models (H1N1 and SARS-CoV-2 Omicron), EB-LNP-based mRNA vaccines elicited potent cytotoxic T-cell activation and durable neutralizing antibody production at low doses. Unlike traditional PEG-LNPs, EB-LNPs show minimal liver distribution, reduced immunogenicity, and improved safety profiles after repeated administrations.By leveraging albumin’s natural trafficking pathway, EB-Lipid represents a transformative delivery platform that combines targeted lymph node delivery with enhanced biosafety, positioning it as a promising candidate for next-generation mRNA vaccines and therapeutics.

Acid-degradable Cationic Lipid (ADC) composed of cationic lipid is synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improves the performance of LNP-mRNA complexes in vitro and in vivo.

SG5 is a dual-amine ionizable lipid developed for systemic, lung-selective mRNA delivery. Its two closely spaced tertiary amines and two C16 beta-hydroxy tails produce two apparent pKa transitions when formulated as fSG5 LNPs, enabling stepwise protonation during endosomal maturation. In mice, fSG5 generated substantially stronger pulmonary luciferase expression than a C12-200/DOTAP comparator and enabled functional Cre mRNA delivery. Delivery of Nrf2 mRNA reduced edema and inflammatory injury in an LPS-induced acute lung injury model. SG5 is a preclinical research lipid for pulmonary RNA delivery and gene-editing studies.

CS22021 is a novel, synthetically engineered ionizable sterol lipid (ISL) developed by CanSino, specifically designed for advanced mRNA delivery via lipid nanoparticles (LNPs). Its core innovation lies in its unique molecular architecture, which integrates a cholesterol moiety directly conjugated to a branched aliphatic tail (derived from ALC-0315) and a hydrophilic headgroup containing tertiary amines. This bifunctional design allows CS22021 to simultaneously fulfill the roles of both the ionizable lipid (for mRNA binding/encapsulation and endosomal escape) and the structural cholesterol component within LNPs. Consequently, CS22021 enables the formulation of highly efficient three-component LNPs (ISL-3C-LNPs), eliminating the need for free cholesterol, using only itself, the phospholipid DOPE (crucial for forming stable, uniform nanoparticles without defects), and a PEGylated lipid. When formulated into LNPs and administered intramuscularly, CS22021 demonstrates a critical property: it achieves localized mRNA expression predominantly at the injection site, significantly minimizing off-target delivery (especially to the liver/spleen) and associated systemic toxicity. Furthermore, mRNA vaccines delivered by CS22021-based LNPs elicit robust and balanced immune responses, including strong antigen-specific IgG antibodies and, notably, a significantly enhanced CD8+ T cell response compared to conventional four-component LNPs. This combination of efficient mRNA encapsulation/delivery, localized expression for improved safety, and potent induction of cellular immunity, particularly CD8+ T cells, positions CS22021 as a highly promising lipid platform, especially for next-generation mRNA vaccine applications like cancer immunotherapy.