| DC67538 |
XH-04
|
XH-04 (Lipid#4) is an ionizable lipid engineered for advanced mRNA delivery developed by JiaChen West Lake Biotech. Its core structure features a central benzene ring with asymmetric hydrophobic tails (C9-C10 chains) and pH-responsive tertiary amines that enable efficient mRNA encapsulation and endosomal escape. As detailed in CN113993839A, XH04 outperforms industry benchmarks (e.g., MC3 lipid), boosting protein expression by >10-fold in BHK cells. In PCT/CN2024/121624, JiaChen further demonstrated its utility in lung-targeted LNPs (tLNP/tLCNP). When combined with cationic lipids (e.g., DOTMA at 2:1 molar ratio), XH 04 redirects >80% of mRNA delivery to murine lungs—overcoming liver tropism—while maintaining low toxicity. The lipid’s benzenic core and optimized alkyl chain geometry (patent claims 1-9) are credited for enhanced endosomal disruption and mRNA release kinetics. JiaChen’s innovations position XH-04 as a cornerstone for next-generation mRNA therapeutics. |
| DC60855 |
4A3-SC7
|
4A3-SC7 is a proprietary, ionizable lipid component central to the SORT LNP platform developed for targeted organ delivery. It features a unique branched-tail structure designed to enhance mRNA encapsulation and endosomal escape. In the study, it served as the primary ionizable lipid in both Liver SORT LNPs and updated Lung SORT LNPs. For liver targeting, it was formulated at 15.04 mol% alongside helper lipids (DOPE: 23.04%, Cholesterol: 38.72%), PEG-lipid (DMG-PEG2000: 3.2%), and the liver-targeting lipid 4A3-Cit (20 mol%). This specific composition (Total lipid:RNA = 20:1 wt/wt) yielded LNPs with ~74 nm size, low PDI (0.17), and high encapsulation efficiency (87%) for large mRNAs like ABE editors (~5000 nt). Its branched-tail architecture was critical for stabilizing nanoparticles encapsulating large RNAs, overcoming a key limitation of previous formulations. 4A3-SC7-based Liver SORT LNPs enabled >40% base editing in hepatocytes in vivo, achieving durable correction of the disease-causing SERPINA1 mutation in PiZ mice and significantly reducing pathological protein aggregates. In the updated DualSORT system, 4A3-SC7 was also paired with DORI (instead of DOTAP) for improved lung targeting, demonstrating its versatility as a foundational ionizable lipid for multi-organ gene editing therapeutics. |
| DC60809 |
6Ac1-C12
|
6Ac1-C12 is an ester-core degradable ionizable cationic lipid designed for mRNA delivery, featuring a unique hexa-acrylate ester core ("6Ac1") conjugated with six N-methyldodecylamine chains ("C12") via solvent-free Michael addition. This branched architecture enables optimal mRNA encapsulation and confers exceptional stability, maintaining consistent ~100 nm particle size for over 30 days at 4°C—crucial for cold-chain storage. With a pKa ≈ 6.0, it facilitates pH-responsive endosomal escape through membrane fusion (80% FRET signal increase at pH 5.5) and efficient cytoplasmic mRNA release.Its composition allows precise organ targeting: in conventional four-component LNPs, 98% hepatic mRNA expression occurs post-IV administration, primarily in endothelial cells (60% transfection efficiency). Cholesterol removal enables lung-specific accumulation and translation via three-component formulations, overcoming historical hepatic off-targeting. The lipid shows negligible cytotoxicity in vitro (>85% cell viability) and no significant organ damage in vivo (ALT/AST/BUN/CREA levels comparable to PBS controls). Its degradable ester core hydrolyzes into smaller metabolites, enhancing biocompatibility. Modular compatibility with DOTAP/DDAB cationic lipids expands applicability for pulmonary or splenic targeting, establishing 6Ac1-C12 as a versatile platform for organ-selective mRNA therapeutics. |
| DC67292 |
IAJD34
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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. |
| DC60793 |
LUMI6
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The LUMI-6 lipid, autonomously designed via the LUMI-lab platform, is a brominated ionizable lipid optimized for mRNA delivery. Formulated at a molar ratio of 35:28:34.5:2 (LUMI-6:DOTAP:cholesterol:C14-PEG2000), LNPs exhibit uniform physicochemical properties, including a hydrodynamic diameter of ~80 nm, polydispersity index (PDI) <0.2, and robust mRNA encapsulation efficiency. In vitro, LUMI-6 LNPs demonstrated 1.8-fold higher transfection potency in human bronchial epithelial cells compared to its debrominated counterpart (LUMI-6D), with minimal cytotoxicity confirmed by CCK-8 assays. In vivo, pulmonary delivery of CRISPR-Cas9 mRNA via LUMI-6 LNPs achieved 20.3% gene editing efficiency in murine lung epithelial cells, surpassing SM-102 (Moderna’s clinical benchmark) and demonstrating preferential tropism for lung epithelium over endothelial cells—critical for inhaled therapies targeting cystic fibrosis and surfactant disorders. The brominated tail enhances endosomal escape through optimized protonation dynamics, though explicit pKa values remain unmeasured. Synthesized via high-throughput combinatorial chemistry and refined through AI-driven active learning, LUMI-6 combines scalable production with organ-selective delivery, positioning it as a transformative platform for pulmonary nucleic acid therapeutics. |
| DC60663 |
Si5-N14
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Si5-N14 is a lipid-based molecule engineered with siloxane groups, designed specifically for efficient mRNA delivery to the lungs. The incorporation of siloxane units boosts the cellular uptake of mRNA-loaded lipid nanoparticles (LNPs) and enhances their ability to escape from endosomes. These properties significantly increase the overall effectiveness of mRNA delivery, making Si5-N14 a promising tool for targeted therapeutic applications. |
| DC65682 |
RCB-4-8
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RCB-4-8 is a biodegradable ionizable lipid nanoparticle (LNP) engineered for efficient pulmonary mRNA delivery and in vivo genome editing, as detailed in the primary research article "Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing" (Li et al., Nature Biotechnology 2023）. Synthesized from a combinatorial library of 720 biodegradable lipids via a three-component reaction system, RCB-4-8 features an alkyne-containing lipid tail and tertiary amine headgroup, optimized through high-throughput screening for superior lung-targeting capabilities. Its unique molecular design incorporates hydrolyzable ester and carbonate groups, enabling rapid biodegradation (<30% lung retention at 48 h vs. >90% for conventional lipids) while maintaining high transfection efficiency. When formulated with DOTAP instead of DOPE, RCB-4-8 LNPs achieved 100-fold higher luciferase mRNA expression in murine lungs compared to FDA-approved MC3 LNPs and mediated 95% GFP knockout in vitro. In Ai9 reporter mice, intratracheal delivery of RCB-4-8 loaded with Cre mRNA edited 53% of total lung cells after three doses, while codelivery with Cas9 mRNA/sgRNA yielded 7.2% tdTomato+ cells, rising to 17% when combined with AAV-sgRNAs. With an optimal particle size of 85.7 nm (PDI 0.11) and >87% mRNA encapsulation, RCB-4-8 supports repeat dosing and represents a transformative platform for inhalable gene therapies targeting congenital lung diseases like cystic fibrosis. |
| DC60489 |
LIPID 331
|
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. |
| DC49907 |
5A2-SC8
|
5A2-SC8 is a dendrimer for miRNA delivery to late-stage liver tumors with low hepatotoxicity. 5A2-SC8 shows potent EC50 < 0.02 mg/kg (siRNA against FVII (siFVII)) in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors. 5A2-SC8 is a degradable lipid-like compound (ester-based dendrimer) for small RNAs delivery.5A2-SC8, was obtained by screening a large library of more than 1500 ester-based dendrimers
containing ionizable amino groups, which have three
tertiary amine heads and five lipid tails. Based on this library,
the in vitro transfection efficiency of different formulations of
5A2-SC8 iLNPs was evaluated, discovering the optimal formulation
(5A2-SC8, DOPE, cholesterol, PEG at a molar ratio of
15:15:30:3) of 5A2-SC8 iLNPs for delivering fumarylacetoacetate
hydrolase (FAH) mRNA to liver.After the intravenous injection
via tail, the model mice of hepatorenal tyrosinemia type I
had strong FAH protein expression, which prevented
body weight loss and increased the survival rate of hepatorenal
tyrosinemia mice . In addition to introducing utility of
5A2-SC8 iLNPs for the therapeutic intervention, the 5A2-SC8
iLNPs containing DOTAP have been used to establish complex
mouse models via intravenous injection, including in situ liverspecific
cancer model and in situ lung-specific cancer model.
Based on this iLNPs delivery system, 5A2-SC8 induced model
construction method overcomes the time-consuming and costly
disadvantages of traditional animal models establishing methods,
including transgenesis and gene engineering in embryonic
stem cells. |
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