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

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 mechanism, offers a promising and chemically distinct strategy to enhance both the efficacy and safety of mRNA vaccines, which is particularly valuable in scenarios of limited vaccine supply and for minimizing potential adverse effects associated with high vaccine dosages.