SL02 is a next-generation ionizable lipid featuring a unique branched hydrophobic domain and a pH-sensitive dimethylaminoethyl headgroup（pKa 6.25）developed by Seqirus. Its asymmetric lipid tails, combining unsaturated and saturated chains, enhance LNP fusogenicity and endosomal membrane disruption. With a slightly lower pKa  than SL01, SL02 achieves efficient mRNA binding at acidic pH while maintaining neutral charge in circulation, reducing nonspecific interactions. In vitro, SL02-LNPs show superior transfection potency in BHK-V cells, attributed to improved cellular uptake and endosomal escape kinetics. In vivo, it elicits high neutralizing antibody titers (comparable to MF59-adjuvanted vaccines) and robust CD8+ T-cell activation. The lipid’s ester-based design ensures biodegradability, while PEGylation compatibility enhances colloidal stability. SL02’s tailored balance of hydrophobicity and ionization enables precise control over nanoparticle size (70–120 nm) and low polydispersity, positioning it as a leading candidate for saRNA-based vaccines and gene therapies.

SL01 is an ionizable cationic lipid compound pKa 6.31）developed by Seqirus, characterized by a biodegradable ester backbone and tertiary amine headgroup, enabling pH-dependent charge modulation. Its structure incorporates twin hydrophobic tails with unsaturated carbon chains, enhancing membrane fluidity and promoting endosomal escape. The lipid’s pKa (~6.5–7.0) optimizes nucleic acid complexation at physiological pH while minimizing cytotoxicity. SL01 demonstrates robust mRNA encapsulation efficiency (~90%) in lipid nanoparticles (LNPs) and facilitates intracellular delivery via endocytosis. Preclinical studies highlight its efficacy in inducing potent humoral and cellular immune responses, particularly in influenza mRNA vaccines. Its ester linkages ensure gradual metabolic clearance, reducing long-term toxicity. SL01-based LNPs exhibit stability in serum and compatibility with scalable manufacturing processes, making it a versatile candidate for therapeutic mRNA delivery.

​​nor-MC3​​ is a novel ionizable lipid develoed by Nanovation, derived from the MC3 structural framework, characterized by two ​​C17 alkyl chains​​ (each containing two Z-geometry double bonds) conjugated to a ​​4-(dimethylamino)butanoate​​ headgroup. Synthesized via a streamlined route involving Claisen condensation of methyl linoleate, hydrolysis/decarboxylation to generate a C17 ketone, reduction to the corresponding alcohol, and final esterification with 4-(dimethylamino)butanoic acid, nor-MC3 retains the ionizable amine functionality critical for pH-dependent nucleic acid binding and endosomal escape. Compared to the benchmark lipid MC3 (C18 chains), nor-MC3 demonstrates ​​superior mRNA delivery efficiency​​ in vitro (2-fold higher luciferase expression at 10 μg/mL mRNA) and enhanced in vivo biodistribution (higher liver and spleen targeting in mice). Notably, its shortened C17 chains challenge conventional assumptions about optimal hydrophobic chain length, offering improved synthetic scalability while maintaining or exceeding MC3's encapsulation efficiency (~95%), nanoparticle size (~80 nm), and low polydispersity (PDI ~0.08). For siRNA delivery, nor-MC3 achieves comparable EC₅₀ values (0.1644 μg/mL vs. MC3’s 0.1308 μg/mL), highlighting its versatility as a next-generation lipid nanoparticle (LNP) component for nucleic acid therapeutics.

IAJD 288(IAJD-288) is a pentaerythritol-based one-component ionizable amphiphilic Janus Dendrimer (IAJD), delivery systems for mRNA delivery.

F10T5 is a tetrahedral tetrahydrofuran (THF)-derived lipid nanoparticle (LNP) engineered with four acid-labile acetal tails, designed for efficient mRNA delivery to the central nervous system. This lipid features a mono-THF core conjugated with branched hydrophobic chains that balance lipophilicity (LogD ≈11) and endosomal escape capability. Preclinical studies demonstrated F10T5 LNPs bypass the blood-brain barrier via meningeal lymphatic vessels (MLVs) after subcutaneous neck injection, showing 40-fold higher brain luciferase expression than FDA-approved SM102 LNPs. Cryo-EM revealed spherical nanoparticles (~170 nm diameter) with 91.9% mRNA encapsulation. In Neuro-2a cells, F10T5 exhibited superior cytoplasmic mRNA release through enhanced endosomal membrane disruption, evidenced by diffuse calcein fluorescence. Flow cytometry confirmed neuron-predicted delivery (8.8% GFP+ neurons vs 1.28% with SM102) in mice, with functional validation in Ai14 transgenic models where Cre mRNA-loaded F10T5 induced tdTomato expression in neurons and glial cells. Safety assessments showed normal hepatic/renal biomarkers and no histopathological abnormalities. The THF core and acetal tail design synergistically optimize lymphatic trafficking, brain penetration, and biodegradability, positioning F10T5 as a transformative platform for mRNA-based therapies targeting neurodegenerative diseases.

A2T2C9 (CP-LC-1465) is an imidazole-based ionizable lipid with branched hydrophobic chains and β-propionate linkers, formulated in four-component LNPs for spleen-targeted mRNA delivery. It achieves >80% spleen selectivity with protein expression exceeding 1×10⁷ p/s in mice, driven by its negative zeta potential (-9.7 to -19 mV). Structural features including imidazole polar head and branched acrylate (C9) enhance splenic tropism, potentially through distinct protein corona interactions. Demonstrated low cytotoxicity (>75% viability in splenic cells) and biodegradability via pH-sensitive linkers enable efficient mRNA delivery without permanent charged additives, outperforming conventional anionic SORT systems in selectivity and therapeutic potential.

76-O17Se is a lipidoid for the efficient delivery of antiCD19 mRNA CAR to murine primary macrophages. 76-O17Se is more efficient than delivery with lipofectamine 2000 (LPF2K) or MC3

CL1H6 is an ionizable lipid designed for advanced nucleic acid delivery, and its lipid nanoparticle formulation, CL1H6-LNP, demonstrates exceptional efficiency in delivering both siRNA and mRNA into NK-92 cells. This innovative system enables precise and effective intracellular delivery, making it a valuable tool for enhancing therapeutic and research applications in natural killer cell biology.

C12-4 (C12-494,Lipid A-4) is a branched-chain ionizable cationic lipidoid that has been used in the formation of lipid nanoparticles (LNPs) for the delivery of mRNA. LNPs containing lipid A4 and encapsulating an mRNA reporter accumulate in the uterus, placenta, and ovaries, as well as to the spleen and liver, in pregnant mouse dams unlike LNPs containing the branched-chain ionizable cationic lipidoid C12-200, which primarily accumulate in the liver. Intravenous administration of LNPs containing lipid A4 and encapsulating mRNA encoding VEGF increase placental VEGFR1 levels and mean fetal blood vessel area without inducing liver damage in pregnant mouse dams.

DIM7S is a sugar-alcohol-derived ionizable lipid with mannitol as the precursor. DIM7S LNP is 10-fold, 30-fold, 20-fold, 4-fold and 3-fold superior in mRNA delivery than Lipo 3K, Electro, ALC-0315, MC3 and SM-102, respectively. DIM7S LNP enables effective CD40 mRNA delivery into human peripheral blood monocyte-derived DCs without obvious cytotoxicity.

GalNAc Lipid 1002 is a trivalent GalNAc-lipid conjugate designed for ASGPR-mediated hepatic delivery. It features a lysine-based scaffold covalently linked to three GalNAc moieties via a ​12-unit PEG spacer, anchored by a ​1,2-O-dioctadecyl-sn-glyceryl (DSG) lipid tail.

GalNAc Lipid 1005 is a trivalent GalNAc-lipid conjugate designed for ASGPR-mediated hepatic delivery. It features a lysine-based scaffold covalently linked to three GalNAc moieties via a ​44-unit PEG spacer, anchored by a ​1,2-O-dioctadecyl-sn-glyceryl (DSG) lipid tail.

Lipid 5D8 is a novel biodegradable ionizable lipid (IL) developed through a combinatorial chemistry strategy to overcome the limitations of conventional lipid nanoparticles (LNPs) in mRNA delivery. Synthesized via a one-step, solvent-free Michael addition reaction between amine and thiol monomers, 5D8 features asymmetric lipid tails and a biodegradable ester backbone, ensuring both structural versatility and reduced toxicity. In preclinical studies, 5D8-based LNPs demonstrated exceptional liver-targeting efficiency and mRNA delivery performance. A single intravenous dose (1 mg/kg) achieved 61% CRISPR-Cas9-mediated editing of the TTR gene in mice, reducing serum TTR protein by 90%, outperforming benchmark lipids like C12-200 (51% editing). Moreover, 5D8 enabled efficient delivery of base editors (ABE8.8 and CBE4max), achieving 42% PCSK9 editing (74% serum protein reduction) and correcting hereditary tyrosinemia in mice, significantly extending survival. Beyond gene editing, 5D8 LNPs effectively delivered siRNA (complete serum TTR clearance at 0.05 mg/kg) and enhanced hepatocyte targeting by enriching apolipoprotein E on particle surfaces. Crucially, 5D8 exhibited superior biocompatibility with no hepatotoxicity (normal ALT/AST levels), contrasting traditional LNPs. Its rapid biodegradability and "plug-and-play" design make 5D8 a versatile platform for mRNA therapeutics, holding broad potential for treating genetic disorders, cardiovascular diseases, and beyond. This innovation represents a critical advancement toward safer, high-efficiency clinical translation of gene-editing therapies.L

BNT-51 is an ionizable thiolipid developed by Biontech, characterized by its sulfur-containing moieties and a multiarm dendron-like architecture. Synthesized via reactions between amine-containing compounds and sulfur-based halides or sulfonates, it forms stable lipid nanoparticles (LNPs) optimized for mRNA delivery. The LNPs exhibit uniform particle size (80–100 nm, PDI <0.2), near-neutral zeta potential, and high mRNA encapsulation efficiency (>90%), while maintaining payload integrity through freeze-thaw cycles and extended storage. In vitro, BNT-51 demonstrates low cytotoxicity (>80% cell viability in C2C12, HepG2, and HEK293 cells) and superior transfection efficiency compared to conventional lipids, particularly in immune cells such as CD4+/CD8+ T cells within PBMCs. Its modular design allows integration of stealth lipids (e.g., PEG or vitamin E derivatives) to prolong circulation time and minimize immune activation, as evidenced by low hemolysis and complement activation risks. In vivo, BNT-51-based LNPs enable targeted mRNA delivery to splenic macrophages, achieving potent genome editing (e.g., Cre mRNA) and therapeutic protein expression (e.g., BACH1) in preclinical models. With its tunable structure, robust stability, and cell-specific tropism, BNT-51 holds promise for advancing mRNA therapeutics in gene editing, cancer immunotherapy, and regenerative medicine, offering a versatile platform for next-generation nanomedicine.

Lipid 17 is a novel, highly potent ionizable lipid designed for mRNA delivery within lipid nanoparticles (LNPs) developed by AstraZeneca . Its structure features a secondary amine head group attached to a cyclic ether moiety (specifically, the 2-oxaspiro[3.3]heptan-6-amine head group). It possesses an asymmetric tail architecture: one tail is derived from heptadecan-9-ol (a branched C17 secondary alcohol), while the other tail is a modified nonyl chain (C9) with a key ethyl branch at the 3-position. The linker connecting the head group to the tails has a length equivalent to n=3 (three methylene units) as defined in the study. This specific combination of the secondary amine cyclic ether head group, asymmetric tails, and the ethyl branch at the 3-position of the nonyl chain proved critical for its exceptional performance. When formulated into LNPs and administered intravenously in mice, Lipid 17 demonstrated a remarkable 6-fold increase in functional protein (eGFP) expression in the liver compared to the benchmark lipid MC3, with high statistical significance (P < 0.0001). This makes Lipid 17 one of the most active lipids identified in the study and a promising candidate for liver-targeted mRNA therapeutics.​​ 

Lipid 19 is an engineered cationic lipid designed to optimize the delivery of RNA within lipid nanoparticles (LNPs) developed by Nitto. Its unique structure—featuring a dual-hydroxyl headgroup and tailored hydrophobic chains—enables highly efficient encapsulation of these fragile genetic payloads, protecting them from degradation. The resulting LNPs exhibit exceptional stability (<100 nm size), target the liver specifically for enhanced therapeutic impact, and support applications ranging from mRNA vaccines to gene-silencing therapies. This makes lipid 19 a pivotal advancement in precision nanomedicine for liver-related disorders.​

​​200Oi10​​ is an ionizable lipidoid used in lipid nanoparticles (LNPs) for RNA delivery. Structurally, it features ester-conjugated cleavable lipid tails, enhancing biodegradability and reducing toxicity compared to non-cleavable analogs. Preclinical studies show that 200Oi10-based LNPs primarily accumulate in the liver (97.7%) after intravenous administration. However, intraperitoneal injection redirects biodistribution, achieving 46.4% pancreatic uptake, which can be further amplified by incorporating cationic lipids like DOTAP. This unique tropism enables pancreas-targeted mRNA delivery. 200Oi10's ester linkages promote rapid clearance, improving biocompatibility while maintaining siRNA/mRNA delivery efficiency. Its design exemplifies the use of degradable lipidoids to balance organ specificity, efficacy, and safety in RNA therapeutics.

18-2-9b2 is a dendron-like degradable ionizable lipid which facilitates mRNA delivery to splenic macrophages. 18-2-9b2 LNP encapsulating therapeutic BTB domain and CNC homologue 1 (BACH1) mRNA exhibited proficient BACH1 expression and subsequent Spic downregulation in splenic red pulp macrophages (RPM) in a Spic-GFP transgene model.

H7T4-4 is an ionizable lipid designed for mRNA delivery via lipid nanoparticles (LNPs). It features a cyclic amine headgroup (derived from cyclen tetrahydrochloride) and four C14 hydrophobic alkyl tails, synthesized through a Michael addition reaction between cyclen and 1,2-epoxytetradecane. With a high transition temperature (Tm = 58.6°C) due to strong intermolecular interactions from its cyclic headgroup and multi-tail structure, H7T4-4 alone forms rigid aggregates incompatible with mRNA encapsulation. However, when blended with low-Tm helper lipids (e.g., DOPE, Tm = -16°C), the system’s overall Tm decreases, enabling stable LNP formation. Optimized formulations (20% H7T4-4, 41% DOPE, 38% cholesterol, 1% DMG-PEG) exhibit efficient mRNA encapsulation (>90%) and transfection. Structural analyses (SAXS, cryo-TEM) confirm monodisperse LNPs with lamellar/hexagonal phases. In vivo, H7T4-4 LNPs show tumor-targeted and intranasal mRNA delivery with reduced off-target accumulation compared to SM-102-based LNPs. This rational design highlights Tm-guided helper lipid selection to overcome rigidity challenges in ionizable lipids.

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.

Lipid B3 is a biodegradable ionizable lipid for liver targeted delivery. Lipid B3-LNP shows high delivery efficacy and low toxicity in delivering RNA to liver cells.

YK-009 is a novel ionizable lipid for mRNA delivery. Comparisons of YK009-LNP-mRNA and commercial MC3-LNP-mRNA showed that YK009-LNP-mRNA vaccines had good biodistribution patterns, favorable tissue clearance, and high delivery efficiency. Furthermore, our study proved that YK009-LNP-Omicron mRNA could trigger a robust immune response and immune protection against the SARS-CoV-2 Omicron variant.

ATX-129 is a novel ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of RNA developed by Arcturus.

ATX-111 is a novel ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of RNA developed by Arcturus.

ATX-132 is a novel ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of RNA developed by Arcturus.

ATX-100 is a novel ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of RNA developed by Arcturus.

ATX-106 is a novel ionizable lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of RNA developed by Arcturus.

HY-501​​ is a next-generation cationically ionizable lipid engineered for high-efficiency RNA delivery developed by Biontech. Formulated at ​​40–50 mol%​​ in lipid nanoparticles (LNPs) alongside DSPC, cholesterol, and polysarcosine-conjugated lipid ​​C14pSar23​​, HY-501 yields uniform, stable particles (80–100 nm) with >90% RNA encapsulation. It demonstrates ​​superior in vivo performance​​: driving 2-fold higher protein expression than benchmark lipids (EA-405/HY-405) in muscle tissue, minimizing off-target liver accumulation, and reducing immunogenic risks (near-zero complement activation and <5% hemolysis). Preclinically, HY-501-based LNPs encoding SARS-CoV-2 spike protein elicit potent neutralizing antibodies and T-cell responses, underscoring its utility in precision vaccines. Its combination of scalable synthesis, exceptional transfection efficiency, and biosafety establishes HY-501 as a transformative vector for therapeutic RNA delivery.

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.