Reprogramming mRNA Delivery Tropism via Nitrogen-To-Sulfur Substitution in Ionizable Lipids.

Abstract

Ionizable lipids serve as critical determinants for mRNA therapeutics. While clinically approved lipids like ALC-0315 demonstrate robust hepatic tropism, their inherent liver-targeting bias substantially limits therapeutic applications requiring extrahepatic delivery. Furthermore, the complex safety validation requirements for novel lipid architectures present significant barriers to clinical translation. Hence, a simple nitrogen-to-sulfur (N-to-S) switching strategy is proposed in the head group of marketed vectors to modulate the tissue distribution of LNP-mRNA. Proof-of-concept studies with ALC-0315-derived S-ALC-0315 reveal that this atomic-level modification fundamentally redirected delivery tropism from hepatic to pulmonary tissues. Notably, formulation optimization demonstrates that combining S-ALC-0315 with its parent lipid at a 1:2 molar ratio generated LNPs with spleen targeting. Consequently, this method promotes the generation of antigen-specific cytotoxic T lymphocytes (CTL), and has produced significant anti-tumor effects in two tumor models while maintaining safety. This research underscores the N-to-S lipid modification as a promising platform for tailoring organ targeting and accelerating clinical translation.