Engineering morphology of tetrasulfide-incorporated mesoporous silica nanoparticles for enhanced mRNA delivery

Lipid nanoparticles (LNPs) are the most studied nanocarrier for mRNA delivery, yet their broader application remains limited due to suboptimal cellular uptake, low efficacy in mRNA delivery, and poor stability. In this study, we report a novel tetrasulfide-incorporated virus-like porous silica (VLPSi) nanoparticle as a safe and efficient platform to enhance LNP-mediated mRNA delivery. By systematically tuning the synthesis parameters, a series of nanoparticles with distinct morphologies and architectures were obtained, enabling the study of how tetrasulfide and particle morphology affect mRNA delivery. The performance of VLPSi was optimized by evaluating cellular uptake, cytotoxicity, and transfection performance with different lipid and mRNA payloads across multiple cell types. The results showed that increasing the length and number of spikes on the VLPSi surface significantly improved cellular uptake efficiency and subsequent mRNA expression. Mechanistically, the enhanced delivery arose from the combined effect from the nanospikes and intracellular tetrasulfide degradation. Furthermore, the nanoparticles significantly enhanced the stability of mRNA. Overall, these findings establish a structure-function relationship between virus-like topography, biodegradable silica chemistry, and mRNA delivery. This work provides a structurally tunable, biodegradable, and highly effective bioinspired nanoplatform to enhance mRNA delivery.