Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects

• DOI: 10.1073/pnas.2309472120
• Publication Date: 2023-12-07T18:34:49Z
• Authors: Jingan Chen; Yue Xu; Muye Zhou; Shufen Xu; Andrew James Varley; Alex Golubovic; Rick Xing Ze Lu; Kevin Chang Wang; Mina Yeganeh; Daniel Vosoughi; Bowen Li
• Keywords: Muscles; Liposomes; Nanoparticles; mRNA Vaccines; Biological Sciences; Transfection

Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding landscape mRNA-based therapies. Nevertheless, risk delivery off-target tissues highlights necessity LNPs with enhanced tissue selectivity. The intricate nature biological systems and inadequate knowledge structure–activity relationships emphasize significance high-throughput methods produce chemically diverse libraries screening. Here, we introduce a streamlined approach rapid design synthesis combinatorial biodegradable ionizable lipids. This led identification iso-A11B5C1, an uniquely apt muscle-specific delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting organs like liver spleen. Moreover, iso-A11B5C1 also exhibited reduced potency lymph nodes antigen-presenting cells, prompting investigation into influence direct immune cell via on vaccine effectiveness. In comparison SM-102, iso-A11B5C1’s limited attenuated its ability elicit humoral immunity, it remained highly effective triggering cellular responses after intramuscular administration, which is further corroborated by strong therapeutic performance as cancer melanoma model. Collectively, our study not only enriches toolkit generating tissue-specific lipids but encourages reassessment prevailing paradigms design. rethinking principles, suggesting that achieving might be sole criterion developing vaccines.