Breaking Endosomal Barriers: Thiol-Mediated Uptake Lipid Nanoparticles for Efficient mRNA Vaccine Delivery

作者：Zhijie Lian, Lingying Zheng, Shuya Liu, Junjie Zhang, Jie J. Zhou, Jun Wu, Songying Ouyang, Jingying Li, Huanghao Yang · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c05367 · 被引用次数：30 · 研究领域：RNA Interference and Gene Delivery、Advanced biosensing and bioanalysis techniques、Viral Infections and Immunology Research

Lipid nanoparticles (LNPs) are the most clinically advanced delivery platforms for mRNA therapeutics; however, their full potential is significantly limited by suboptimal intracellular mRNA delivery. Herein, we report the rational chemical design and synthesis of a dithiolane-incorporated lipidoid (S-DOPE) to construct an innovative LNP formulation, termed SLNP, for enhanced intracellular mRNA delivery. These chemically engineered SLNPs exploit an inherent thiol-mediated uptake mechanism, whereby the unique dithiolane moiety triggers a dynamic covalent disulfide-thiol exchange reaction with cell surface thiols. This chemically driven reaction facilitates direct cytosolic mRNA delivery, effectively bypassing endosomal entrapment, a major bottleneck for conventional LNPs. In vitro studies demonstrate that SLNP formulations achieve an 11-fold increase in mRNA transfection and translation efficiency compared to standard LNPs. Furthermore, in vivo evaluations reveal a 4.5-fold enhancement in mRNA expression and robust immune responses. SLNP-mediated vaccination at low doses elicits high titers of neutralizing antibodies and a Th1-biased T-cell response. Notably, SLNPs induce neutralizing antibody titers against the SARS-CoV-2 spike protein that are comparable to those achieved with significantly higher doses of conventional LNPs, highlighting their substantial dose-sparing potential. These findings establish that SLNP, by leveraging the chemically innovative thiol-mediated uptake ...