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.

DORI, N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium bromide, is an ionizable cationic lipid with lower cytotoxicity and high transfection efficiency. Reagent grade, for research use only.

304O13 is a novel Biodegradable lipidoid for RNA delivery.

Lipid 854 is an ionizable cationic lipid that has been used in the generation of lipid nanoparticles (LNPs) for the delivery of mRNA in vivo. Lipid 854 has been optimized based on Lipid 88.

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.

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).

E10i-494 is a branched ionizable lipid designed to enhance the delivery of mRNA and CRISPR-Cas9 ribonucleoprotein (RNP) complexes. It belongs to the Branched Endosomal Disruptor (BEND) lipid family, which features terminal branching to improve endosomal escape and cellular uptake.E10i-494 demonstrated exceptional performance in T cell engineering, achieving >80% transfection efficiency in primary human T cells. This is significantly higher than the ~70% efficiency achieved by the linear lipid C14-494.The isopropyl branch enhances the lipid's ability to penetrate and disrupt endosomal membranes, leading to improved release of mRNA and RNPs into the cytoplasm.Despite its high efficiency, E10i-494 exhibits low cytotoxicity, making it suitable for therapeutic applications.E10i-494 is particularly effective for delivering mRNA to T cells, making it a promising tool for CAR-T cell therapy and other immunotherapies.Its ability to deliver CRISPR-Cas9 RNPs efficiently also makes it suitable for in vivo gene editing applications.

IAJD-34 is a one-component ionizable amphiphilic Janus dendrimer specifically engineered for targeted mRNA delivery to the lung parenchyma, as described by Meshanni et al. in Nature Communications article "Targeted delivery of TGF-β mRNA to murine lung parenchyma using one-component ionizable amphiphilic Janus Dendrimers" . This synthetic nanoparticle self-assembles with mRNA through simple mixing in acetate buffer, forming stable dendrimersomes approximately 93-97 nm in size with high encapsulation efficiency (>95%) and a positive zeta potential (~48 mV). Its defining feature, highlighted in the study, is exceptional lung tropism after intravenous injection, enabling significantly higher luciferase expression in murine lungs compared to other organs. As demonstrated by Meshanni et al., IAJD 34 effectively delivers therapeutic mRNA (e.g., TGF-β mRNA) to the lower lung, inducing transient protein production with minimal systemic toxicity at appropriate doses (e.g., 10 µg), offering a promising strategy for treating parenchymal lung diseases.

Lipid 331 is a biodegradable cyclic ionizable lipid. LNPs containing Lipid 331 result in robust transfection in the nasal and lung tissues of mice and efficient transfection of lung epithelial cells and lung-resident APCs. Lipid 331 is a promising candidate for mRNA vaccine delivery, offering the potential for further enhancing the potency of mRNA vaccines.

​​C-a16​​ is an ionizable lipid engineered through Mannich reaction chemistry, designed to revolutionize mRNA delivery by synergizing high efficiency with minimized immune activation. Synthesized by reacting a phenolic tail derivative, formaldehyde, and a branched tertiary amine core under optimized ethanol conditions, this lipid integrates antioxidant phenol groups directly into its structure. These phenol moieties serve as intrinsic radical scavengers, effectively neutralizing intracellular reactive oxygen species that typically degrade mRNA and trigger inflammation.In lipid nanoparticle formulations, C-a16 constitutes the functional backbone, enabling superior mRNA encapsulation efficiency while maintaining a stable nanoparticle size of approximately 80–100 nm. Critically, it outperforms conventional lipids like DLin-MC3-DMA by achieving significantly higher target-protein expression in vivo alongside markedly reduced pro-inflammatory cytokine secretion. The antioxidant capability is not incidental but fundamental—quenching the phenol groups drastically diminishes both ROS suppression and delivery efficacy, confirming the design's mechanistic elegance.C-a16 represents a paradigm shift: its biomimetic antioxidant architecture addresses the chronic trade-off between delivery potency and immunogenicity, unlocking safer therapeutic applications for vaccines and gene therapies.

Lipid B1​ is a next-generation ionizable lipid engineered for superior mRNA delivery, featuring a patented ​β-isobutylglutarate branching linker​ that optimizes nanoparticle assembly and intracellular release. Its unique structure combines a pH-responsive tertiary amine headgroup with twin C18 alkyl tails connected via biodegradable ester bonds, enabling precise control over lipid packing and endosomal escape. Preclinical studies demonstrate that Lipid B1-based LNPs (bLNPs) achieve ​**>75% transfection efficiency in vitro​ at ultra-low mRNA doses (1 μg), outperforming commercial benchmarks like SM-102. In vivo, subcutaneous administration of bLNPs delivers ​10-fold higher luciferase expression**​ than linear-chain analogs, with targeted biodistribution to lymph nodes and tumor sites. Clinically relevant data show 100% tumor prevention in prophylactic cancer vaccine models and 70% tumor regression in therapeutic settings when combined with checkpoint inhibitors. The ester-based backbone ensures rapid metabolic clearance, minimizing systemic toxicity risks (NOAEL >10 mg/kg in mice). Compatible with mRNA, siRNA, and CRISPR-Cas9 payloads, Lipid B1 is ideal for vaccines, gene therapies, and immuno-oncology. Its scalable 3-step synthesis (yield >80%) and lyophilization stability (-80°C, 12 months) make it a cost-effective solution for GMP-grade production. For advanced delivery with unmatched safety and efficacy, Lipid B1 sets a new standard in nucleic acid therapeutics.

PPz-2R1 is an ionizable cationic lipid engineered for mRNA delivery via lipid nanoparticles (LNPs). These LNPs demonstrate remarkable lung-selective accumulation in mice, showing significantly higher uptake compared to heart, liver, spleen, and kidney tissues. When loaded with PTEN mRNA, PPz-2R1 LNPs effectively restore tumor suppressor function in PTEN-deficient lung cancer cells and inhibit tumor progression in orthotopic models, with enhanced efficacy observed in combination with PD-1 blockade therapy.

(+)CP-LC-0729 is an cationic lipid derived from CP-LC-0729 and achieves significantly higher expression and selectivity highlights the advantages of this lipid system for lung-targeted delivery.

FO35 is an artificial intelligence-guided designed ionizable lipid for RNA delivery to the muscle, lung and nose. FO-35 LNPs enable potent transfection throughout the whole ferret lung epithelium, from trachea to alveoli.

FO-32 is an artificial intelligence-guided designed ionizable lipid for RNA delivery to the muscle, lung and nose. FO-32 LNPs enable potent transfection throughout the whole ferret lung epithelium, from trachea to alveoli.

306-N16B is a lipidnanoparticle, and allows systemic codelivery of Cas9 mRNA and sgRNA. 306-N16B can transport mRNA to the pulmonaryendothelial cell. 306-N16B can be used for research of genome editing-based therapies. Based on the same lipid libraries with 306-O12B, the researchers also found that N-series ionizable lipids were able to selectively deliver mRNA to the lungs of mice. Compared with the liver-targeted O-series ionizable lipids which contained ester bond in lipid tail found in previous work, such as 306-O12B, the N-series ionizable lipids with the lipid tail containing amide bond prefer to deliver mRNA to the lung. As a N-series ionizable lipid, the chemical structure of the 306-N16B is shown in Figure 4a,b. The difference of organ targeting may be due to their adsorption of different protein coronas during blood circulation caused by their different structures mentioned earlier.It has shown that the second major protein of the protein corona adsorbed by liver-targeting 306-O12B iLNPs was apolipoprotein E (ApoE), while the three dominant proteins in the protein corona adsorbed by lung-targeting 306-N16B iLNPs were serum albumin, fibrinogen beta chain, and fibrinogen gamma chain. However, the 306-N16B iLNPs showed less organ selectivity when systematically codelivered Cas9 mRNA and sgRNA in vivo, which could simultaneously activate tdTomato expression in the liver and lung of Ai14 mice, whereas single mRNA delivery could almost exclusively deliver mRNA to the lungs. This surprising phenomenon requires further investigation. Both the change of iLNPs charge and the change of lipids functional group can influence the distribution of iLNPs in vivo due to the altering of protein corona composition. Therefore, it is possible to control the organ targeting of iLNPs by controlling the composition of the outer protein corona of iLNPs.

L649 is a next-generation, lung-targeting ionizable lipid specifically designed for systemic mRNA delivery developed by Hopewell. Belonging to the novel "N-series" lipid class, it features a unique structure with an amine-containing head group and hydrophobic tails incorporating amide bonds. This design enables L649 to form highly stable lipid nanoparticles (LNPs) that exhibit exceptional tropism for the lower respiratory tract (lungs, bronchi, trachea) following intravenous administration. It demonstrates superior efficiency in delivering therapeutic payloads (like mRNA) specifically to key lung cell types, including alveolar epithelial cells (AT1 and AT2) and bronchial cells, while minimizing off-target accumulation in organs like the liver. L649-based LNPs, particularly when formulated with helper lipids like POPE, combine high potency with significantly improved tolerability, allowing for effective dosing in vivo. This makes L649 a promising candidate for developing treatments for various lung diseases such as pulmonary fibrosis, COPD, lung cancer, and infectious diseases like COVID-19.​

IR-117-17 (A10-LIN) is an ionizable and biodegradable lipid specifically designed for nebulized mRNA delivery. When formulated into lipid nanoparticles (LNPs), IR-117-17 demonstrates remarkable efficacy, achieving a 300-fold enhancement in lung mRNA delivery compared to the best-performing LNP previously reported. Additionally, it shows a two-fold improvement over the leading PBAE-based delivery system, with up to a 45-fold increase in mRNA delivery efficiency to the large airways.

THOR 76​​ is an ionizable lipid developed for lung-targeted mRNA delivery, synthesized via a high-throughput Ugi four-component reaction (U4CR). It combines spermine (N3, amine core), oleyl aldehyde (A2), oleic acid (C2), and a morpholine-functionalized isonitrile (D3). Remarkably, its ​​crude reaction mixture​​ outperforms purified forms in efficacy, suggesting synergistic impurities or intermediates enhance function. Formulated into lipid nanoparticles (LNPs) with cholesterol, DOPE, and PEG-lipid, THOR 76 LNPs exhibit ​​exceptional lung tropism​​ with secondary spleen affinity after intravenous administration. They efficiently transfect ​​pulmonary endothelial cells​​, enabling robust gene expression (e.g., Cre recombinase) and significant CRISPR-Cas9-mediated gene editing (1.22% at 0.1 mg/kg dose) in the lungs. With a particle size <150 nm, positive zeta potential, and >90% mRNA encapsulation, THOR 76 achieves targeted delivery while minimizing off-target effects in the liver. Its design overcomes limitations of cationic helper lipids, offering a potent, tolerable platform for treating pulmonary genetic disorders and cancers.

Lipid CAD9 (3-A2-7b is a cationic degradable (CAD) lipid. 3-A2-7b formulated LNP, LNP-CAD9, can deliver FLuc mRNA to the lungs in vivo. LNP-CAD9 co-delivering Cas9 mRNA/VEGFR2 single guide RNA (sgRNA) effectively induces VEGFR2 knock out in lung endothelial cells of female mice.

A3T2C7 (CP-LC-1495) is a biodegradable ionizable lipid featuring three β-propionate linkers and an azetidine polar head, formulated in four-component LNPs. It demonstrates exceptional lung-targeted mRNA delivery with 97.1% selectivity and high protein expression (1.21×10⁸ p/s) in mice. Its slightly positive zeta potential (~3.5 mV) correlates with lung tropism, likely mediated by protein corona enrichment of vitronectin and prothrombin. The β-propionate structure enables pH-sensitive biodegradability for enhanced endosomal escape while maintaining low cytotoxicity (>90% cell viability). This lipid enables organ-specific mRNA delivery without permanently charged additives, outperforming conventional SORT strategies in selectivity and expression efficiency.

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.

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. 

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.

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.

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.

F11T6 is a next-generation lipid nanoparticle (LNP) optimized for ultra-efficient neuron-targeted mRNA delivery, featuring a dual-tetrahydrofuran (THF) core and four pH-responsive acetal tails. Its unique bis-THF architecture enhances lipid bilayer stability and promotes brain-specific biodistribution, achieving ​​16.4% GFP+ neurons​​ in vivo—the highest reported among CNS-targeting LNPs. Cryo-EM reveals a compact spherical structure (Ø~150 nm) with 93.2% mRNA encapsulation efficiency, while THF-acetal synergy enables rapid endosomal escape (Pearson coefficient: 0.16 vs. 0.27 for F10T5). Preclinical studies show F11T6 leverages meningeal lymphatic transport for brain accumulation, yielding ​​13.0% neuron-specific tdTomato expression​​ in Ai14 mice, surpassing F10T5 (8.93%) and SM102 (0.1%). Mechanistically, the dual-THF core strengthens interactions with lipoprotein receptors on brain endothelial cells, whereas acetal tails undergo acid-triggered hydrolysis in endosomes, releasing mRNA into the cytoplasm. Despite slightly higher liver/spleen accumulation than F10T5, toxicology assessments confirm no hepatorenal toxicity (BUN/ALT/AST within normal ranges) or histopathological changes. Co-localization analyses demonstrate superior penetration into deep brain regions like the hippocampus, critical for treating neurodegenerative disorders. With a LogD of 12.3, F11T6 balances lipid solubility and biodegradability, outperforming clinical benchmarks in both efficiency (40× SM102) and neuron specificity. This platform holds transformative potential for delivering CRISPR-Cas9, siRNA, or neurotrophic factors, particularly in diseases demanding high-dose CNS transfection with minimal off-target effects.

H9 is a new ionizable lipid driven from AI-Guided Ionizable Lipid Engineering (AGILE) platform for mRNA delivery. H9 LNPs shows superior mRNA transfection potency compared to LNPs containing (D-Lin-MC3-DMA).