IAJD 294 is a ​​single-component ionizable amphiphilic Janus dendrimer​​ that autonomously coassembles with mRNA via simple injection into uniform monodisperse dendrimersome nanoparticles (DNPs, 85 nm diameter, PDI<0.2), eliminating complex multi-component formulations. Its optimized ​​3,5-benzoyl ester linkage​​ and symmetric hydrophobic tails enable ​​dual-organ targeting​​: ​Spleen​​: 2.97 × 10⁷ RLU (50% of total activity) ​​Lymph nodes​​: 10⁶ RLU (10× higher than IAJD 87) through ​​partial hydrophobic interdigitation​​ (stabilizing DNPs for enhanced lymphatic uptake) and ​​pKa ~6.5​​ (facilitating endosomal escape), validating constitutional isomerism for precision delivery.

HCQ-4​​ is a rationally engineered ionizable lipid derived from hydroxychloroquine (HCQ), featuring a ​​ditetradecylamine-derived twin-C14 saturated hydrocarbon tail​​ linked to the HCQ headgroup via a ​​succinic acid spacer​​. Synthesized through a three-step route involving HCQ deprotonation, ditetradecylamine carboxylation, and EDC/DMAP-mediated amidation, this lipid forms the core of optimized lipid nanoparticles (LNPs) at a molar ratio of ​​60:10:40:0.5 (HCQ-4:DOPE:cholesterol:DMG PEG₂₀₀₀)​​. The structure enables dual functionality: (1) ​​Spleen-selective mRNA delivery​​ (2.3-fold higher splenic vs. hepatic transfection) via 80-100 nm particle size, near-neutral charge (-3 mV), and low PEG density, facilitating immune cell uptake; (2) ​​Tumor microenvironment modulation​​ through HCQ-mediated repolarization of M2 macrophages to antitumor M1 phenotype (iNOS⁺ cells ↑2.5-fold, CD206⁺ cells ↓60%). This bifunctional design synergistically enhances mRNA cancer vaccine efficacy, demonstrating superior prophylactic/therapeutic antitumor activity and antimetastatic effects compared to clinical benchmarks like MC-3 LNP.

Westgene lipid 8 is a cationic lipid featuring a tertiary amine core with three alkyl chains (C1-C15) and two unsaturated C18 linoleate-like tails. Its ionizable amine enables pH-dependent charge for mRNA encapsulation in LNPs. Key structural elements include branched alkyl groups (X1/X2: C4, X3: C2) and ester-linked unsaturated R1/R2 chains, enhancing membrane fusion and endosomal escape. N Used in lipid nanoparticles (LNPs) with DOPE, cholesterol, and PEG-DMG, it demonstrates low cytotoxicity, high mRNA delivery efficiency, and spleen-targeted immune activation, making it suitable for vaccine/therapeutic delivery.

A28-C6B2 is an ionizable lipid (pKa 6.43) designed for mRNA encapsulation in lipid nanoparticles (LNPs). Following intravenous injection in mice, these LNPs exhibit spleen-selective accumulation, particularly localizing in F4/80+ macrophages and CD11c+ dendritic cells, with moderate uptake by T lymphocytes.

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.

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.

Sail Lipid 2231 is a novel ionizable lipid targeting to spleen developed by Sai Biomedicine.As described on US20250205167A1 Lipid 2231 features  a ​​pyrrolidine core​​ (5-membered ring) with biodegradable ester linkages and asymmetric C17/C11 hydrophobic chains. In vivo data shows moderate spleen targeting (Spleen RLU: ​​3.8E+06​​) with a spleen-to-liver ratio of ​​12.767​​. 

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.

E8i-200 is a novel Branched Endosomal Disruptor (BEND) ionizable lipid, designed to enhance the efficiency of lipid nanoparticles (LNPs) in drug delivery, particularly for mRNA and protein delivery. Its unique structure, featuring terminal branching, improves endosomal escape, a critical step in the delivery of therapeutic cargo into cells.E8i-200 is designed to enhance endosomal escape, a key bottleneck in mRNA and protein delivery. Its terminal branching structure provides several advantages:Improved Endosomal Membrane Penetration: The branched structure allows E8i-200 to more effectively disrupt endosomal membranes, facilitating the release of mRNA and proteins into the cytoplasm.Enhanced Gene Editing Efficiency: E8i-200 has been shown to significantly improve the delivery of CRISPR-Cas9 ribonucleoprotein (RNP) complexes, enabling efficient gene editing in vivo.E8i-200 significantly enhanced mRNA expression in the liver, outperforming traditional linear lipids like C12-200 in mouse models.E8i-200 effectively delivered CRISPR-Cas9 RNP complexes, achieving high editing efficiency in the liver, surpassing that of linear lipids.E8i-200 also showed high transfection efficiency and low cytotoxicity in T cells, making it a promising candidate for CAR-T cell engineering and other immunotherapies.

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.

ORNA lipid 144​​ is a novel ionizable lipid engineered for splenic RNA delivery developed by ORNA Therapeutics, featuring a biodegradable structure with a protonatable tertiary amine headgroup and ester-linked branched C14 alkyl chains. This design enables exceptional spleen-targeting capability, demonstrated by 3-fold higher luciferase expression in the spleen compared to benchmark lipids and near-complete B-cell depletion when delivering anti-CD19 CAR circRNA. It forms highly stable lipid nanoparticles maintaining homogeneous size (60–80 nm) and low polydispersity across diverse manufacturing conditions and buffer systems. Rapid clearance from the liver and spleen minimizes off-target accumulation, while high circRNA encapsulation efficiency (>90%) and pH-dependent endosomal escape make it ideal for immunotherapies and vaccines requiring precise splenic bioavailability and sustained efficacy.

AX6​​ is an ionizable lipid in the ​​F32 LNP​​ formulation, engineered by ReNAgade/Orna Therapeutics for targeted mRNA delivery to T cells. AX-6's unique ​​bridged bicyclic/polycyclic core​​ with a ​​tertiary amine group​​ enables pH-dependent protonation and endosomal escape, while ​​C14-C18 hydrophobic tails​​ (optionally branched/fluorinated) enhance bilayer stability and mRNA encapsulation. Demonstrating ​​exceptional T-cell tropism​​, AX6 achieves high transfection efficiency in CD4+/CD8+ T cells (validated in NHP/humanized models) with minimal toxicity. Compared to clinical benchmarks (SM-102, ALC-0315), its rigid core offers superior ​​serum stability​​ and ​​immune-cell specificity​​, positioning it as an ideal candidate for ​​CAR-T/NK therapies​​ and ​​next-gen vaccines​​. The F32 LNP system's proven efficacy (e.g., in vivo B-cell depletion) underscores AX 6's transformative potential for ​​cell engineering​​ and ​​immunotherapies​​.

Sanofi Lipid 15 is a highly efficient ionizable cationic lipid for T-cell transfection. Its unique structure enables superior mRNA delivery to T cells, with key features including: 1) pH-responsive ionization (pKa ~6.5-7.2) for optimal endosomal escape, 2) biodegradable ester linkages for reduced toxicity, and 3) optimized hydrophobic tails for membrane fusion. When formulated in LNPs with CD3/CD8-targeting antibodies, Lipid 15 achieves >50% transfection efficiency in primary human T cells, with 2-3× higher GFP expression than DLin-KC3-DMA controls. The LNPs maintain stable particle size (~100nm) after freeze-thaw cycles and show minimal off-target effects (<5% non-T cell transfection). This performance makes Lipid 15 ideal for CAR-T and TCR engineering applications.

CL15F 9-5, a piperidine-based ionizable lipid, exhibits favorable properties for mRNA delivery in lipid nanoparticles (LNPs). Its apparent pKa ranges between 6.24–7.15, ideal for mRNA encapsulation and endosomal escape. LNPs formulated with CL15F 9-5 (50:38.5:10:1.5 molar ratio of ionizable lipid:cholesterol:DSPC:DMG-PEG2k) demonstrated high mRNA encapsulation efficiency (>90%) and maintained physicochemical stability (size, PDI, zeta potential) during storage at 4°C for 5 months . In vitro, CL15F 9-5 LNPs showed superior luciferase expression in HEK-293T cells compared to CL4F-based LNPs. In vivo, liver-targeted LNPs delivered hEPO mRNA effectively, with sustained serum hEPO levels post-storage. Intravenous administration of FLuc mRNA-loaded CL15F 9-5 LNPs yielded strong hepatic bioluminescence, confirming liver tropism. As a vaccine candidate, CL15F 9-5 induced robust antigen-specific cellular immunity in mice, with a 14-fold increase in IFN-γ spots compared to SM-102. Its enhanced stability is attributed to reduced aldehyde impurities, minimizing mRNA-lipid adduct formation.

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.

PL-40​​ is a ​​cardiolipin-mimetic ionizable lipid​​ engineered for high-efficiency, antibody-free mRNA delivery to T cells. PL 40 LNPs exhibit a mean particle size of ​​120 nm​​, zeta potential of ​​-5.19 mV​​, and >80% mRNA encapsulation efficiency, with excellent plasma stability (≤5% size change after 6h in serum). Cryo-TEM reveals ​​polyhedral nanoparticles​​ with phase-separated domains, while SAXS confirms tight mRNA packing (d-spacing: ​​~3 nm​​ vs. 6.64 nm in conventional LNPs). AFM demonstrates exceptional rigidity (high bending modulus), enabling T cell-selective uptake via actin-mediated endocytosis (>2× higher than ALC0315 LNPs).In primary human T cells, PL40 LNPs achieve ​​>90% transfection​​ at 0.5 μg mRNA dose and sustain >100× higher luciferase expression than benchmark lipids. When delivering circular RNA, they extend protein expression ​​>5 days​​ with superior spleen tropism (spleen:liver ratio = ​​2.63​​). Crucially, they reprogram T cells into functional CAR-Ts in vivo without antibody conjugation, evading exhaustion markers (no Tim-3/PD-1 upregulation). Therapeutically, PL40-based uPAR-targeted CAR mRNA reduces liver fibrosis (​​collagen↓50%​​, ALT↓50%) and rheumatoid arthritis severity (​​clinical scores↓60%​​) by clearing senescent cells. Humanized anti-uPAR CARs delivered via PL40 show near-complete cytotoxicity (>95%) against uPAR+ cells, underscoring clinical translatability.

Lipid C14-A1 is an ionizable lipid. C14-A1-LPN is a potent and safe LNP platform to deliver Foxp3 mRNA to CD4+ T cells to engineer immunosuppressive FP3T cells.

Lipid 8 iLNPs were used to deliver CRISPR-Cas9 mRNA and sgRNA which targeted to the PLK1 gene. The safety and excellent intracerebral diffusion performance of lipid 8 iLNPs ensured that the survival of murine glioblastoma multiforme (GBM) mice was extended. The median survival was extended by approximately 50% and the overall survival was increased by 30%. The treatment of metastatic adenocarcinoma was executed by the EGFRtargeted lipid 8 iLNPs. These iLNPs possessed the ability of tumor targeting, which could increase the accumulation of CRISPR-Cas9 mRNA and sgRNA within the tumor cells. After a single intraperitoneal administration,
80% PLK1 gene was edited and the overall survival of mice with high-grade ovarian cancer malignant ascites was enhanced by
80% . These results demonstrate the clinical potential of CRISPR-Cas9 gene editing system can be delivered by iLNPs for treating tumors, and provide new ideas for tumor gene therapy.

OF-C4-Deg-Lin is a novel ionizable lipid for RNA delivery. OF-C4-Deg-Lin LNPs entrapping mRNA coding for luciferase induce the majority of protein expression in the spleen, with minimal translation in the liver, and negligible translation in other organs. OF-C4-Deg-Lin LNPs entrapping mRNA coding for luciferase induce the majority of protein expression in the spleen, with minimal translation in the liver, and negligible translation in other organs. To improve the mRNA delivery to extrahepatic tissues, a series of degradable diketopiperazine-based ionizable lipids were synthesized. Through evaluating the mRNA functional activity delivered by iLNPs, it was found that the ionizable lipids with doubly unsaturated lipid tails and linkers containing a length of four carbon aliphatic chain (Of-C4-Deg-Lin) could deliver the mRNA more efficiently. Moreover, compared with cKK-E12 and Invivofectamine, Of-C4-Deg-Lin could specifically induce more than 85% of firefly luciferase expression in spleen,minimal expression in the liver, and insignificant expression in other tissues.

CICL-242​ is a constrained ionizable cationic lipid highlighted in patent US 20250127728A1 as a promising candidate for advanced therapeutic delivery, particularly in stem cell and gene editing applications. Its structure features a rigid amine headgroup similar to CICL-207, which likely facilitates efficient endosomal escape and reduces non-specific uptake, enhancing targeted nucleic acid delivery. Although detailed performance data is not fully disclosed in the patent, CICL-242 is explicitly synthesized and included in gene editing experimental systems (e.g., CRISPR-Cas9 workflows), suggesting its potential for high-efficiency transfection in hard-to-transfect cells​ like hematopoietic stem cells (CD34⁺). This makes it a strong candidate for ex vivo cell engineering and regenerative medicine, where precision and low off-target effects are critical. While further validation is needed to quantify its efficacy and safety profile, CICL-242 represents a strategic innovation in the lipid library for next-generation genetic therapies.

Based on the data from patent US 20250127728A1, CICL-238​ emerges as a highly promising ionizable lipid candidate, demonstrating notable advantages for targeted delivery applications. It achieves exceptional transfection efficiency—reaching approximately 90% of CICL-207's performance in splenic T-cells even at a reduced lipid ratio of 50% in LNP formulations. Additionally, CICL-238 exhibits minimal off-target expression​ in hepatocytes (<8%, comparable to CICL-207), underscoring its enhanced specificity for immune cells over liver tissues. Its optimized structure likely contributes to efficient endosomal escape and reduced Kupffer cell uptake, making it ideal for liver-related therapies​ (e.g., siRNA silencing for metabolic diseases) and potentially broadening applications to genetic medicine where precision and safety are paramount. Further validation in disease models could solidify its role as a versatile, low-toxicity alternative to benchmark lipids.

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.

2Ac3-C18 is a unique ionizable lipid with a distinct degradable core structure：featuring 2 acrylate units and 3 amine groups—linked to a C18 alkyl chain. Its LNPs (formulated with DOPE/cholesterol/DMG-PEG2000) exhibit spleen-specific mRNA delivery in vivo.

Lipid te AA3-Dlin is a novel ionizable lipid developed for mRNA-LNP vaccines.When formulated into LNPs, te AA3-Dlin demonstrates excellent stability in serum and protects encapsulated mRNA from degradation. A key feature is its unique protein corona profile, with high ApoE abundance, which is crucial for efficient in vivo targeting, particularly to the spleen. This enables potent dendritic cell transfection, leading to enhanced antigen presentation and robust cytotoxic T-cell responses for superior antitumor immunity.

The PyCB (Pyridine Carboxybetaine) lipid 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.

Lipid A-12 is an ionizable cationic lipid from Capstan Therapeutics and a close analog of CICL-1 (L829). The key structural distinction is in the headgroup spacer length, where the value of 'n' is 1 in A-12, compared to 0 in CICL-1 (L829).

NC-TNP (noncationic thiourea lipids nanoparticles) could compress mRNA by strong hydrogen bonds interaction between thiourea groups of NC-TNP and the phosphate groups of mRNA. NC-TNP could escape the recycling pathway to inhibit the egress of internalized nanoparticles from the intracellular compartment to the extracellular milieu. NC-TNP-encapsulated mRNA shows higher gene transfection efficiency in vitro and in vivo than mRNA-LNP formulation. NC-TNP also shows spleen targeting delivery ability with higher accumulation ratio (spleen/liver), compared with traditional LNP.The C18 non-cationic thiourea lipid self-assembles into ~100 nm nanoparticles with neutral surface charge, utilizing strong hydrogen bonding between its thiourea groups and mRNA phosphate groups for efficient mRNA complexation. This delivery system demonstrates significantly enhanced EGFP expression efficiency—2.3-fold higher than standard C6/C12 formulations—in DC2.4, B16, and 4T1 cells, while sustaining luciferase activity for over 20 days post-subcutaneous injection. It exhibits exceptional stability, maintaining >94% mRNA integrity and <10% particle size variation after 30-day lyophilized storage. Importantly, the nanoparticles show pronounced spleen-targeting capability with 20-fold greater accumulation in the spleen versus liver, effectively activating twice the level of antigen-specific CD8⁺ T cells. Critically, the system avoids cationic lipid-associated toxicity, inducing no detectable IL-6/CXCL10 inflammation and causing no histopathological damage in cardiac or splenic tissues, thus establishing a novel high-efficacy, low-toxicity mRNA delivery platform.

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.

​​Lipid 10a-26​​ is an ionizable lipid developed by Orna Therapeutics for lipid nanoparticle (LNP) formulations. It features a biodegradable ester backbone and an ionizable headgroup, enabling efficient encapsulation and delivery of circular RNA (oRNA). Experimental data show that Lipid 10a-26 mediates robust protein expression in hepatocytes and immune cells (e.g., T cells), with strong liver-targeting specificity observed in vivo. Its optimized hydrolysis profile ensures stable oRNA delivery and reduced immunogenicity. For instance, LNPs formulated with Lipid 10a-26 (molar ratio 50:10:38.5:1.5) demonstrate high transfection efficiency in splenic B cells and sustained therapeutic protein production.The lipid’s design balances efficacy and safety, making it ideal for applications like CAR-T therapy and hepatic protein replacement.