RNA cancer-vaccine research

​TOT-5​​, a tri-oleoyl-Tris ionizable lipid (pKa 6.2), enables splenic B cell-targeted mRNA delivery via 15% DSPC-incorporated LNPs. Its charge-neutral, hydrophobic surface minimizes hepatic ApoE uptake and enhances complement C3 adsorption, facilitating CD21/35-mediated uptake by marginal zone B cells. In vivo, intravenous 15%DSPC-LNPs showed 8-fold higher spleen-to-liver luciferase expression vs 3%DSPC, with anti-CD21/35 blocking 60% B cell uptake. Intramuscular administration induced robust OVA-specific IgG (10^5 titer) and CTL responses (3.5% tetramer+ CD8+ T cells) while reducing hepatotoxicity (ALT/AST levels ≤40 U/L vs SM-102-LNPs' 80-120 U/L). Cryo-ET confirmed stable lamellar structures (80-100 nm, ζ-potential -2 mV). This formulation achieves safe, ligand-free splenic targeting for mRNA vaccines.

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.

E12LA6B603（ILB3132，ILB-3132） is a novel ionizable amino lipid disclosed in patent WO2024198497A1, developed by MagicRNA, representing a highly efficient component for lipid nanoparticle (LNP) delivery systems.When formulated into LNPs, E12LA6B603 LNP achieves a remarkable 98.26% encapsulation efficiency for mRNA. It mediates superior in vitro transfection in dendritic cells (1.8E+05 intensity) and demonstrates best-in-class in vivo protein expression after intramuscular injection (2.2E+09 intensity). Most notably, in a B16-OVA melanoma model, therapeutic OVA-mRNA vaccines delivered by E12LA6B603 LNPs induced 100% complete tumor regression, highlighting its superior efficacy over benchmarks like DLin-MC3 and SM-102. Its biodegradable ester linkages and balanced structure make it a promising, potent candidate for next-generation mRNA vaccines and therapeutics.

AMG514 is a spirocyclic diamine ionizable lipid developed for spleen-biased mRNA delivery. In the cited mouse experiments, AMG514 LNPs produced approximately four-fold higher splenic reporter expression than a cKK-E12 comparator, transfected splenic dendritic cells and macrophages, and were evaluated for co-delivery of antigen and immune-remodeling mRNAs. The authors associated its approximately 7.5 apparent LNP pKa and serum- or plasma-derived protein-corona profile with the observed biodistribution, but did not establish a single causal targeting mechanism. All formulation and performance information shown below is literature-derived study evidence, not a product specification or a guarantee of reproducible LNP performance.

ALC-0315 is an ionisable aminolipid that used for mRNA compaction and aids mRNA cellular delivery. ALC-0315 can be used to form lipid nanoparticle (LNP) delivery vehicles.

SM-102 is an ionizable amino lipid that has been used in combination with other lipids in the formation of lipid nanoparticles.Administration of luciferase mRNA in SM-102-containing lipid nanoparticles induces hepatic luciferase expression in mice. Formulations containing SM-102 have been used in the development of lipid nanoparticles for delivery of mRNA-based vaccines.

C12-200 is a well-known cationic lipid used in the formulation of lipid nanoparticles (LNPs) for the delivery of therapeutic nucleic acids, including siRNA, mRNA, and CRISPR components. It is widely recognized for its high in vivo potency at low doses and is often used as a positive control ionizable lipid in research exploring new ionizable lipids.

Iso-A11B5C1 is an asymmetric Ugi-reaction-derived ionizable lipid selected for muscle-focused mRNA delivery. In the cited mouse study, its optimized LNP produced muscle expression comparable to an SM-102 benchmark after intramuscular administration while showing no measurable reporter expression in the examined off-target organs. The same formulation delivered Cre mRNA for localized muscle gene editing and was evaluated with model-antigen and cancer-vaccine mRNAs. All formulation and performance information shown below is literature-derived study evidence, not a product specification or a guarantee of reproducible LNP performance.

C18 NC-TNP is a novel noncationic thiourea lipid without positively charged groups. It binds nucleic acids via hydrogen bonds instead of electrostatic attraction, avoiding cation-triggered systemic inflammation. Formulated into nanoparticles, it efficiently encapsulates mRNA, siRNA and plasmids, shows excellent serum tolerance and long-term liquid/lyophilized storage stability. It enters cells mainly through macropinocytosis, escapes endosomes intact to reduce nucleic acid degradation. In vivo, it targets spleen preferentially, induces robust long-lasting Th1-type cellular and humoral immunity with minimal organ toxicity, superior to SM102 LNPs for mRNA cancer vaccine delivery.

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.

DMA4-H228 is a novel, biodegradable lipidoid specifically engineered for spleen-targeted mRNA delivery.​​ Its structure combines a dimethylamino (DMA4) headgroup with a unique hyperbranched lipid tail (H228) synthesized via Michael addition, incorporating ester bonds for enhanced biodegradability. This design enables the formation of stable lipid nanoparticles (LNPs) (~170 nm) with high mRNA encapsulation efficiency (>96%). Critically, DMA4-H228 exhibits exceptional intrinsic tropism for the spleen (>98% targeting efficiency after IV administration), requiring no external targeting ligands. It selectively delivers mRNA to splenic antigen-presenting cells (APCs), including dendritic cells, macrophages, and B cells. This triggers potent immune activation: rapid IFNα secretion, upregulation of APC maturation markers (CD86/CD40), and robust antigen-specific immune responses. Demonstrating significant therapeutic potential, DMA4-H228-based mRNA vaccines effectively inhibit tumor growth in melanoma models (e.g., B16F10-OVA). This correlates with increased tumor-infiltrating CD8⁺ T cells, a shift towards pro-inflammatory M1 macrophages, elevated antigen-specific antibodies (IgG), and strong T cell responses (evidenced by IFNγ⁺ spots). Its ability to bypass liver tropism and directly activate splenic APCs makes DMA4-H228 a powerful platform for next-generation mRNA vaccines and cancer immunotherapy.

TE AA3-Dlin is an optimized lipid nanoparticle (LNP) carrier designed for mRNA-based cancer immunotherapy, enabling precise in vivo dendritic cell (DC) reprogramming to enhance antitumor immunity. TE AA3-Dlin LNP exhibits superior serum stability, maintaining consistent particle size and low turbidity under physiological conditions, while protecting mRNA from degradation, which is crucial for effective delivery. Functionally, TE AA3-Dlin preferentially targets splenic DCs by leveraging ApoE-enriched protein coronas, facilitating efficient cellular uptake and mRNA expression, as demonstrated by enhanced EGFP signals in DCs.This targeting promotes DC maturation, antigen presentation, and membrane-bound IL-15 expression, activating cytotoxic T lymphocytes (CTLs) for tumor rejection. In models like melanoma and colon carcinoma, it synergizes with checkpoint inhibitors, showing minimal toxicity and robust immunological memory.

H5T5 is a leading ionizable lipid nanoparticle (LNP) formulation optimized for in vivomRNA delivery, featuring a pKa of 6.51, a size of ~154 nm, and a narrow polydispersity index (PDI) of 0.05. It demonstrated superior in vitromRNA transfection efficiency in primary immune cells, such as bone marrow-derived macrophages. Following intravenous administration, H5T5 exhibits precise organotropism, predominantly targeting the spleen and bone marrow, where it effectively delivers mRNA to a broad spectrum of immune cells, including macrophages, dendritic cells, T cells, B cells, and NK cells. This capability enables its core application: the in vivogeneration of "pan-CAR" immune cells. When loaded with anti-HER2 CAR mRNA, the H5T5-based therapy achieved potent tumor regression and prolonged survival in multiple solid tumor models. Preliminary safety assessments indicated a manageable cytokine profile and no significant organ toxicity, positioning it as a promising platform for in vivocell engineering.

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.

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.

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.

Lipid88​​ is a high-performance, novel ionizable lipid component engineered for advanced mRNA-LNP vaccine delivery. LNP88 formulation demonstrates superior biodistribution, achieving >10-fold higher transfection efficiency in spleen and lymph nodes compared to benchmark lipids like ALC-0315 via intramuscular delivery. When encapsulating antigen-encoding mRNA (e.g., optimized mCSA construct), Lipid-88 based LNPs drive robust humoral and cellular immunity, enabling complete protection against challenging SARS-CoV-2 variants (WA1/2020, Omicron BA.1, BQ.1) in preclinical models. Its design prioritizes potent immunogenicity with favorable safety profiles.

A28-C6B2 is a biodegradable ionizable lipid specifically engineered for spleen-targeted delivery. Through its unique branched structure, it bypasses hepatic uptake to achieve highly efficient transfection of F4/80+ macrophages and CD11c+ dendritic cells within the spleen. This lipid remains neutral in the bloodstream to minimize non-specific interactions, while undergoing protonation in the acidic environment of the endosome to facilitate nucleic acid release, thereby significantly enhancing the potency of mRNA vaccines and immunotherapies.

​​DM3-BTA-14​​ is a cationic lipid compound engineered for high-efficiency mRNA delivery developed by Hefei AlphaNA Biotechnology. Its structure features a rigid benzene-1,3,5-tricarboxamide core linked to a protonatable dimethylamino headgroup (-N(CH₃)₂) via a propylene spacer (-CH₂CH₂CH₂-) and two saturated C14 alkyl chains. This design enables ≈90% endosomal escape efficiency , superior lymph node targeting for vaccines , and effective tumor-specific mRNA delivery . It outperforms benchmark lipids while maintaining low cytotoxicity, forming stable nanoparticles with cholesterol/DSPC/DSPE-PEG (50:39:10:1 ratio) for therapeutic applications.

Sail Lipid 2308​ is a novel ionizable lipid targeting to spleen developed by Sai Biomedicine.As described on US20250205167A1, Lipid 2308 was designed with a ​​piperidine core​​ (6-membered ring) and asymmetric C17/C11 chains, this lipid achieves unprecedented ​​spleen-specificity​​. It demonstrates dominant spleen accumulation (Spleen RLU: ​​7.8E+06​​, 91.8% of total signal) with a record ​​spleen-to-liver ratio of 112.7​​ (9× higher than 2231). Despite lower protein expression (hEPO: 11,000 ng/mL), near-zero liver uptake (Liver RLU: 66,000) makes Lipid 2308 unparalleled for vaccine/immunotherapy applications targeting splenic immune cells.

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.

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.

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.

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.

113-O12B LNP, an LN-targeting LNP delivery system, is developed for a mRNA cancer vaccine.

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.

A2-Iso5-2DC18 is a top-performing lipid for mRNA delivery in bone marrow-derived dendritic cells (BMDCs), BMDMs and HeLa cells.

A18-Iso5-2DC18 that could not only deliver mRNA vaccines robustly but also activate the stimulator of interferon genes (STING) pathway.

A12-Iso5-2DC18 is a novel amine containing lipid can be used for mRNA delivery, activate the stimulator of interferon genes (STING) pathway, and exhibit anti-tumor immunity.

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.

YK-TLR-001 is a cyclic acetal-based ionizable lipid for mRNA delivery. YK-TLR-001 LNPs are demonstrated to enhance mRNA expression in the spleens and to induce exceptional maturation of antigen-presenting cells (APCs) and to promote antigen presentation.

113-AA-C8C14 is a spleen-tropic ionizable lipid with inherent splenic organ selectivity. Its formulated LNPs drastically reduce off-target liver uptake and drive 57-fold higher mRNA expression in spleen versus benchmark LNPs. It preferentially delivers nucleic acids to splenic immune cells like macrophages and T lymphocytes, supporting in vivo CAR-T engineering and mRNA vaccine research with minimal accumulation in other visceral organs.

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.

C12-2aN is a crosslinked ionizable lipid developed for mRNA vaccine delivery and dendritic-cell metabolic reprogramming. Its structure combines two piperazine-based ionizable amine cores, a bis-amidine crosslinker, and four hydroxylated C12 hydrophobic tails. When formulated with DOPE, cholesterol, and C14-PEG2000, C12-2aN LNPs enhanced mRNA endosomal escape and activated AMPK–mTORC2-dependent glycolysis, supporting dendritic-cell maturation and antigen presentation. In preclinical mouse studies, C12-2aN LNPs generated robust humoral and cellular immune responses in SARS-CoV-2 RBD and OVA cancer-vaccine models. The formulation also demonstrated reduced liver-associated off-target expression and lower acute inflammatory markers than the tested control formulations. C12-2aN is a preclinical research lipid intended for evaluating metabolically active mRNA vaccine delivery systems.

ST12 is a lipid-conjugated DMXAA prodrug designed for temporally controlled STING activation in mRNA vaccine formulations. Its structure integrates a mouse-specific STING agonist, a biodegradable ester linker, an RNA-interacting tertiary amine domain, and two hydrophobic tails. When incorporated as a partial replacement for SM-102, ST12 preserves early antigen mRNA translation and subsequently releases DMXAA to activate STING. This delayed activation supports localized type I interferon signaling, enhanced antigen-specific CD8-positive T-cell responses, and improved antitumor immunity. In preclinical OVA and HPV tumor models, ST12-based Syn-STING vaccines suppressed tumor growth and prolonged survival. ST12 remains a preclinical research lipid developed specifically around DMXAA-sensitive STING systems.

KC3-OA, chemically known as 3-((S)-2,2-di((Z)-octadec-9-en-1-yl)-1,3-dioxolan-4-yl)-N,N-dimethylpropan-1-amine, is an ionizable cationic lipid (ICL) optimized for lipid nanoparticle (LNP) formulations in nucleic acid delivery, particularly for mRNA vaccines. It features a unique structure with mono-unsaturated alkyl chains (C18:1), which enhances oxidative stability compared to polyunsaturated analogs like KC3, while maintaining efficient membrane fusion and endosomal escape capabilities. In LNP compositions, KC3-OA is typically incorporated at 46–54 mol% of total lipids, with an N/P ratio of 4–6 relative to mRNA, ensuring high encapsulation efficiency and transfection potency. Experimental data demonstrate that KC3-OA-based LNPs achieve superior mRNA expression in human dendritic cells, outperforming alternatives like KC3-PA or KC3-01 in both in vitro and in vivo models. For instance, in FIG. 2, KC3-OA LNPs showed ~2-fold higher mCherry expression at low mRNA doses (0.1 μg/mL) due to improved cellular uptake and reduced degradation. Its synergy with anionic phospholipids like DPPS (5 mol%) further enhances dendritic cell targeting via receptor-mediated internalization, leading to robust CD4+ and CD8+ T-cell responses against Mycobacterium tuberculosis antigens. This balance of stability, efficiency, and immunogenicity makes KC3-OA a leading candidate for next-generation vaccines.

C6mPhE-383 is a top-performing ionizable lipid featuring an aromatic ring and a bioreducible disulfide bond. Formulated into lipid nanoparticles, it preferentially delivers mRNA to lymphoid tissues (lymph nodes/spleen) while minimizing off-target liver accumulation after intramuscular injection. In a SARS-CoV-2 vaccine study, it elicited strong antibody responses, promoted protective effector memory T cells, and exhibited enhanced safety by significantly reducing systemic inflammatory cytokines compared to the standard SM-102 LNP.

Lipid 7669 is a premium, spleen-tropic ionizable lipid highly validated in US2025/0049948A1 for targeted mRNA delivery. Engineered for extrahepatic targeting, it achieves exceptional splenic protein expression while minimizing hepatic accumulation, significantly outperforming conventional liver-targeting lipids like MC3 and C12-200. In vivo bioluminescence data confirms its superior whole-body transfection efficiency and highly selective spleen tropism. This high-performance lipid is ideal for pioneering research in mRNA vaccines, splenic immune editing, and autoimmune disease therapies requiring precise extrahepatic delivery. Lipid 7669 is for research purpose.

A1-EP10-O18A​​ is an ​​asymmetric ionizable lipid​​ developed by Starna Therapeutics for mRNA vaccine delivery. Synthesized via Michael addition between amine alcohols and acrylates, its optimized structure—combining a hydrophilic C10 chain and hydrophobic unsaturated C18 tail—enables pH-dependent ionization. As the core component of the ​​STAR0225 lipid nanoparticle (LNP)​​ platform, it efficiently encapsulates mRNA and facilitates endosomal escape. Preclinical studies demonstrate superior in vivo mRNA delivery (vs. commercial SM102 LNPs), with enhanced local biodistribution and minimal off-target accumulation. This lipid underpins ​​STR-V003​​, an RSV prefusion F mRNA vaccine showing robust immunogenicity and protection in animal models, supporting its clinical transition (NCT06344975).

OF-Deg-Lin is a biodegradable lipid containing an ester group, developed from the nonbiodegradable, linoleic acid derived OF-02; mRNA-LNPs containing OF-Deg-Lin showed high expression in the spleen.

C12-TLRa is an adjuvant lipidoid. C12-TLRa substitution can enhance the immunogenicity of clinically relevant SARS-CoV-2 mRNA-LNP vaccines, which holds translational potential.

12T-O14 is a amidine-incorporated degradable (AID) lipid for versatile mRNA delivery. 12T-O14-LNPs mediate efficient intramuscular delivery of mRNA vaccines and systemic delivery of mRNA therapeutics without noticeable toxicity. 12T-O14 serves as a superior supplementary lipid to redirect liver-tropic LNPs to selectively target the lung or spleen via simple adjustment of the formulation.

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.

Lipid I97 is a vitamin B5-derived ionizable lipid for mRNA vaccine delivery. Lipid I97 LNP specifically delivers the mRNA to the spleen and lymph nodes in model mice, induces balanced Th1/Th2 immune responses, and elicits the production of high levels of neutralizing antibodies with low toxicity.

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.

E12CA1A3 is an ionizable cationic lipid (pKa = 6.4) that has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA in vitro and in vivo.1 LNPs containing E12CA1A3 and encapsulating an mRNA reporter induce luciferase reporter expression in mouse bone marrow-derived dendritic cells (BMDCs) and mice. LNPs containing E12CA1A3 are cleared more rapidly from the liver than LNPs containing DLin-MC3-DMA (Item No. 34364) in mice.

AA2 lipid is an innovative amino alcohol-derived ionizable lipid designed for optimized mRNA delivery. Its unique structure includes a hydroxyl-containing headgroup that enhances mRNA binding through hydrogen bonds and a branched ester tail (R2) that promotes a cone-shaped architecture, facilitating efficient endosomal escape. Formulated into lipid nanoparticles (LNPs) with a size of 108.6 ± 3.7 nm and a polydispersity index (PDI) below 0.3, AA2 achieves high mRNA encapsulation efficiency (89.0 ± 1.4%) and an ideal pKa of approximately 6.2, ensuring effective endosomal release.In vivo studies demonstrate that AA2 LNP-encapsulated spike mRNA elicits 4.7-fold higher IgG titers and robust CD8+ T-cell responses (characterized by IFN-γ+, TNF-α+, and granzyme B+ markers) compared to SM-102/ALC-0315 LNPs. Notably, AA2 exhibits minimal off-target accumulation, with low biodistribution in the liver and spleen. Its slightly positive surface charge (+3–5 mV) enhances cellular uptake, while the biodegradable ester structure ensures metabolic clearance, reducing potential toxicity.

The AA15 lipid, an amino acid-derived ionizable lipid, integrates a carboxylic acid-containing headgroup and biodegradable branched ester tails (R2) to enhance mRNA delivery. Optimized as AA15V LNP, it exhibits a hydrodynamic diameter of 102.3 ± 4.1 nm, low polydispersity (PDI <0.15), and slightly positive zeta potential (+4–6 mV), enabling efficient tumor-targeted delivery. With a pKa ~6.1–6.4, AA15V ensures protonation in acidic endosomes, promoting mRNA release. It achieves >85% mRNA encapsulation efficiency, critical for stable saRNA delivery. In vitro, AA15V LNP-sSE-SCTs induced sustained SE-SCT expression (69% H-2Kb+β2m+ B16F10 cells at 72 h), outperforming mRNA formulations. In vivo, a single intratumoral dose of AA15V LNP-sSE-SCTs suppressed tumor growth by 22-fold in vaccinated mice, synergizing with checkpoint inhibitors (anti-PD-1/CTLA-4) for complete regression in 28.6% of lymphoma models. Ex vivo, AA15V enabled SE-SCT expression in human glioblastoma (7.1% CD45− cells) and lung cancer samples (5.8–8.7%), underscoring clinical potential. Key data: pKa ~6.3; encapsulation: 85–89%; zeta: +4–6 mV; size: 102.3 ± 4.1 nm.

Derived from the natural amino acid homocysteine, CP-LC-1422 is an ionizable cationic lipid that enables robust in vivo delivery of various RNA forms (mRNA, cRNA, and saRNA), driving high protein expression. When formulated into LNPs (50/38.5/10/1.5 molar ratio of ionizable lipid/cholesterol/DOPE/PEG-lipid), it achieves superior spleen-specific targeting compared to commercial options through intravenous administration, while maintaining an excellent safety profile.

Derived from the natural amino acid homocysteine, CP-LC-1428 is an ionizable cationic lipid that enables highly efficient in vivo delivery of multiple RNA formats (including mRNA, cRNA and saRNA) with robust protein expression. When formulated into standard LNPs (50:38.5:10:1.5 molar ratio of ionizable lipid:cholesterol:DOPE:PEG-lipid), it demonstrates superior spleen-selective targeting compared to conventional delivery systems following intravenous administration, while maintaining an excellent safety profile.

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.

SAL12 is a novel ionizable lipid derivative that integrates a non-nucleotide STING agonist (agonist 6) with an amino lipid tail through an ester bond, forming the core component of specialized lipid nanoparticles (SAL12-LNPs). These nanoparticles are designed for dual functionality: they efficiently encapsulate and deliver mRNA into dendritic cells while concurrently activating the STING pathway to stimulate innate immunity.

GL5 is an ionizable guanidine-based lipid nanoparticle (G-LNP) designed for superior mRNA delivery. Its guanidinocarbonyl-pyrrole (GCP) headgroup enables pH-responsive behavior and strong mRNA binding via bidentate hydrogen bonds. The cholesterol-free GL5-3 formulation forms compact, stable nanoparticles (~90-120 nm) that exhibit excellent spleen-targeting capability after intravenous injection.GL5-LNPs efficiently deliver mRNA to antigen-presenting cells (APCs), enhancing antigen presentation and T cell activation. In cancer immunotherapy models, GL5-based mRNA vaccines provided complete tumor protection and induced durable immune memory. The platform also enables mRNA delivery to other organs like the pancreas via different administration routes, demonstrating remarkable versatility and therapeutic potential.

(4S)-KEL12​​ is a novel, biodegradable ionizable lipid developed for advanced mRNA vaccine delivery. It was rationally designed by incorporating both a ketal group in the linker and ester segments in the hydrophobic tails, a dual-degradable strategy aimed at enhancing its safety profile. Through iterative optimization, (4S)-KEL12 was identified as a lead candidate with an optimal pKa value of approximately 6.78, which is crucial for efficient mRNA encapsulation and endosomal release.