Imidazole cholesterol ester (ICE) is a sterol‑based ionizable cationic lipid invented by Translate‑Bio (WO2018/089790 A1) for mRNA‑loaded lipid‑nanoparticle (LNP) pulmonary delivery. It fuses an imidazole pH‑responsive headgroup with cholesterol via ester linkage. Typically formulated as a three‑component LNP (ICE : DOPE : DMG‑PEG2K = 60 : 35 : 5 mol ratio), ICE‑LNPs achieve high mRNA encapsulation (>80‑90 %), good nebulization stability and low toxicity. Upon cellular uptake, imidazole mediates endosomal escape; the ester bond degrades to yield cholesterol, conferring favorable biocompatibility. Animal studies demonstrate robust CFTR protein expression in bronchial and alveolar lung tissue after inhalation, making ICE promising for cystic‑fibrosis mRNA therapy.

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.

MIC2 is a set of multi-charged lipids with four tertiary amino nitrogen atoms (4N4T) which could be constructed and applied to form novel lipid nanoparticles developed by Westgen. 4N4T-LNPs based on MIC2 exhibit much higher mRNA translation efficiency than the approved SM-102-LNPs. 4N4T-LNPs are successfully applied to DS mRNA vaccine and the vaccines worked well against SARS-CoV-2 and its variants, including Delta and Omicron.

246C10 is a synthesized ionizable lipid. 246C10 can be formulated into lipid nanoparticles (LNPs) with dioleoylphosphatidylethanolamine (DOPE), cholesterol, and C16-PEG2000 ceramide (PEG-lipid) as well as mRNA. The lipid nanoparticle formulations can be used for mRNA delivery. To obtain iLNPs that could specifically target liver sinusoidal endothelial cells (LSECs), six different ionizable lipids (241C10 to 246C10) were synthesized by an epoxide ring-opening reaction with piperazine- or piperidine-containing amines. Biodistribution and gene regulation of various iLNPs were assessed in vivo, and the results showed that the 246C10 iLNPs (containing piperazine amine) had the highest luciferase expression in the liver. When further analyzing the 246C10 iLNPs transfection efficiency in different types of liver cells, it was found that tdTomato fluorescence was mainly concentrated in hepatocytes, not in LSECs. Figure 6f shows that 80% of hepatocytes are fluorescent, 40% of LSECs are fluorescent, and 20% of Kupffer cells are fluorescent. Due to the mannose receptor on LSECs, mannose-PEG lipid was introduced into 246C10 iLNPs to alter the distribution of iLNPs in different liver cells. As shown in Figure 6g, tdTomato fluorescence distribution was 15% of hepatocytes, 70% of LSECs, and 15% of Kupffer cells, significantly improved the ability of iLNPs to actively target LSECs. In contrast, this work indirectly shows that the iLNPs with piperazine head lipid are more able to deliver mRNA to the liver and translate the target protein than the iLNPs with piperidine head lipid. It is worth mentioning that the preparation buffer of 246C10 iLNPs could influence the encapsulation efficiency of mRNA. With the addition of sodium chloride in the citrate buffer, the encapsulation efficiency of CRISPR-Cas9 mRNA and sgRNA was increased. These iLNPs were able to treat hemophilia safely, without causing hepatotoxicity, the immune response induced by Cas9 and off-target editing.

11-10-8 is an ionizable cationic lipid (pKa = 6.22) that has been used in the generation of lipid nanoparticles (LNPs) for mRNA delivery in vivo.1 LNPs containing 11-10-8 and encapsulating mRNA encoding the Cas9 nuclease and small-guide RNA (sgRNA) targeting transthyretin (TTR), a thyroid hormone carrier protein, decrease serum levels of TTR in mice. LNPs containing 11-10-8 and encapsulating mRNA encoding human fibroblast growth factor 21 (hFGF21) increase serum levels of hFGF21, decrease body and liver weights, and reduce the liver steatosis score in a mouse model of obesity induced by a high-fat diet.

FL0445 is a biodegradable, multi-branched ionizable lipid featuring an ionizable amine-containing headgroup together with ester and carbonate linkages. When formulated with DOPE, cholesterol, and a PEG lipid, FL0445-LNP enabled efficient delivery of both linear mRNA and structurally constrained capped circular RNA (Cap-cirRNA). In the reported study, the optimized formulation produced substantially higher in vitro protein expression than benchmark LNPs based on MC3, SM-102, or ALC-0315 and demonstrated functional nucleic-acid delivery following intravenous, intramuscular, and subcutaneous administration in mice. The platform was also evaluated for mRNA vaccination, ASO-mediated gene silencing, pDNA delivery, and GLP-1-encoding Cap-cirRNA. FL0445-LNP induced comparatively low inflammatory cytokine responses and showed favorable single-dose tolerability in the tested mouse models, supporting its further evaluation as a versatile preclinical delivery lipid for mRNA, circular RNA, and other nucleic-acid modalities.

KC-34 (SPC-A9) is a novel stereopure, diketopiperazine-based ionizable cationic lipid engineered to overcome traditional liver-restricted delivery, achieving balanced multi-organ mRNA transfection. Upon systemic intravenous administration, its precisely optimized chiral configuration allows the lipid nanoparticles (LNPs) to efficiently cross endothelial barriers and target the bone marrow, offering immense therapeutic potential for in vivo hematopoietic stem cell gene editing. Concurrently, KC-34 mediates robust and long-lasting protein expression in the spleen and lungs with minimal hepatic off-target toxicity. Its stable structure provides excellent biocompatibility and high in vivo tolerance, making it ideal for systemic, multi-dose mRNA therapies.

L52715 is a novel ionizable lipid developed by Shanghai Vitalgen, used to deliver mRNA.

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.

CVL1 (C24), also known as VitE-C4DE-Pip-S, is a vitamin E-derived ionizable lipid developed for lipid nanoparticle-mediated delivery of mRNA and other nucleic acids developed by CureVac. It features two hydrophobic α-tocopherol moieties connected to a bis-piperidine ionizable core through biodegradable succinate ester linkages, while a central thioether-containing spacer provides additional structural flexibility. CVL1 can be incorporated into LNP formulations to support nucleic acid encapsulation, cellular uptake, and intracellular delivery. CureVac has investigated CVL1-containing LNPs for mRNA expression in immune-related tissues and cells, including the spleen, lymph nodes, and antigen-presenting cells, making it a valuable research lipid for mRNA vaccines, cancer immunotherapy, and other nucleic acid delivery applications.

MoChol is a cationic cholesterol derivative used as a membrane component in charge-reversible amphoteric nanoliposomes. It has been incorporated with CHEMS, DOPE and POPC into liposomal formulations for the delivery of anti-BCL-2 antisense oligonucleotides.

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.

C14-306 is a rationally designed ionizable lipid for brain targeting delivery, characterized by a linear 3,3'-diamino-N-methyldipropylamine (306) core conjugated with tetradecyl (C14) tails. This specific architectural configuration, synthesized via epoxide ring-opening amination, yields a molecular structure that optimally balances hydrophobic character and protonation capacity. The C14 alkyl chains enhance membrane integration and LNP stability, while the multiamine core facilitates efficient mRNA complexation and pH-dependent endosomal disruption. When formulated into LNPs with standard helper lipids (DOPE, cholesterol, DMG-PEG2000), C14-306-based nanoparticles exhibit favorable physicochemical properties, including a monodisperse size distribution near 110 nm and high mRNA encapsulation efficiency (>84%). High-throughput in vivo barcoding screening identified C14-306 LNPs as lead candidates for brain delivery, demonstrating a significant tropism for neuronal cells over liver tissue. In validation studies, LNPs incorporating C14-306 achieved a 6.9-fold increase in luciferase mRNA transfection in the mouse brain compared to the SM-102 benchmark, coupled with a substantial reduction in hepatic off-target expression. Flow cytometry confirmed preferential transfection of NeuN+ neurons, and safety assessments indicated no significant blood-brain barrier compromise or induction of systemic inflammation. The efficacy of C14-306 is attributed to its tailored pKa, promoting extended circulation and enhanced endosomal escape within brain cells. C14-306 represents a promising platform for systemic mRNA therapeutics targeting neurological disorders.

A4B4-S3 is a novel biodegradable ionizable lipid that has been meticulously designed through modular platforms and optimized specifically for mRNA delivery. It serves as a critical component of lipid nanoparticles (LNPs) and enhances mRNA delivery efficiency by facilitating endosomal escape. The structural design of A4B4-S3 leverages the Passerini reaction, a highly efficient and modular chemical method that enables the rapid generation of diverse lipid libraries. The design focuses on optimizing the methylene units between lipid headgroups and linkages to strengthen hydrogen bonding interactions with mRNA ribophosphate complexes. This enhanced hydrogen bonding allows for more effective release of mRNA from endosomes, thereby boosting delivery efficiency. Concurrently, the structural optimization improves biodegradability, reducing potential long-term toxicity risks. In experimental studies, A4B4-S3 has demonstrated superior gene editing efficacy in mouse liver compared to SM-102, a clinically prevalent lipid used in Moderna's COVID-19 vaccine. It also shows potential for repeat-dose protein replacement therapies, suggesting enhanced stability and safety for long-term treatment regimens. Technologically, A4B4-S3 not only provides a more efficient LNP formulation but also deepens the understanding of the relationship between structure and delivery efficiency. This offers new directions for the development of future mRNA therapeutics. In summary, A4B4-S3 represents a next-generation delivery carrier achieved through rational design and high-throughput screening strategies. Its performance enhancements and biodegradable properties position it as a promising candidate for gene therapies and vaccine applications.

306Oi10 is a branched ionizable lipid that can be used to construct lipid nanoparticles (LNPs) for delivering messenger RNA. The surface ionization of lipid nanoparticles is related to the effectiveness of mRNA delivery. The tail of 306Oi10 has a one-carbon branch, which provides it with stronger surface ionization compared to lipids with linear tails, thereby enhancing its mRNA delivery efficacy. 306Oi10 can be used in research related to mRNA delivery.

A2C18_D5 is an optimized lipid nanoparticle (LNP) component engineered with structural modifications to enhance mRNA delivery efficiency and safety. Its design incorporates a hydrophobic head group (A2, featuring a pentyl chain) and an unsaturated C18 tail, which collectively lower its pKa to the ideal range of 6–7, enabling stable encapsulation of nucleic acids and improved endosomal escape. In vitro and in vivo studies demonstrate that A2C18_D5 achieves mRNA delivery efficiency comparable to the clinically approved LNP benchmark MC3, while exhibiting over 200-fold higher potency than its precursor lipid (A1C11). The lipid’s reduced protonation capacity minimizes cytotoxicity and hemolytic risk, aligning with safety profiles of established LNPs. Upon intravenous administration, A2C18_D5 predominantly targets the liver and spleen, with a biodistribution profile favoring hepatic delivery. Its balanced combination of high transfection efficiency, low toxicity, and favorable pharmacokinetics positions A2C18_D5 as a promising candidate for next-generation mRNA therapeutics, including vaccines and treatments for liver-specific diseases. Further optimization of its head-tail structure highlights its versatility for tailored delivery applications.

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.

Ionizable lipid-2 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 ALC-0315 analogue retains its ionizable tertiary amine, hydroxybutyl headgroup, and dual branched hydrophobic tails, while replacing the two ester linkages with carbonate groups. This modification may alter hydrolytic stability, biodegradability, membrane interactions, and overall LNP delivery performance.