Reprogramming mRNA Delivery Tropism via Nitrogen‐To‐Sulfur Substitution in Ionizable Lipids
Abstract
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.
Article Details
Authors (19)
Xing Duan
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Hai Huang
Shengbin Liu
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Jingkai Gu
Shugang Qin
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Shanhui Jiang
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Chunli Yang
Mengran Guo
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Xi He
Xiaoling Yin
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Zhongshan He
Departments of Critical Care Medicine, Anesthesiology and Translational Neuroscience Center, and Clinical Pharmacy, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital (Z.H., Y. Luo, W.Z., X.H., H.S., C.J., Y.K., X.S.), Sichuan University.
Yuting Chen
Department of Chemistry
Haixing Shi
Departments of Critical Care Medicine, Anesthesiology and Translational Neuroscience Center, and Clinical Pharmacy, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital (Z.H., Y. Luo, W.Z., X.H., H.S., C.J., Y.K., X.S.), Sichuan University.
Tingting Song
Xia Guo
Shenzhen Campus of Sun Yat-sen University
Zhaohui Jin
Zhongwei Zhang
National Laboratory of Solid State Microstructures, School of Physics and Collaborative Innovation Center of Advanced Microstructures
Yongmei Xie
Department of Critical Care Medicine Frontiers Science Center for Disease‐related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu 610041 China
Xiangrong Song