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.
Duan et al. (Fri,) studied this question.
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