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.

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.

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.

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.

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.

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.