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.
Cat.No
DC60782
Name
Lipid A4B4-S3
Chemical Properties
CAS
Formula
MW
Storage
References
Rational design and modular synthesis of biodegradable ionizable lipids via the Passerini reaction for mRNA delivery-Yue Xu # 1, Fanglin Gong # 2, Alex Golubovic # 1, Amy Strilchuk 1, Jingan Chen 2, Muye Zhou 1, Songtao Dong 1, Breanna Seto 3, Bowen LiProc Natl Acad Sci U S A . 2025 Feb 4;122(5):e2409572122. doi: 10.1073/pnas.2409572122. Epub 2025 Jan 30.
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