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

Abstract

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.

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BibTeX RIS

BibTeX

@misc{cao2026engineering,
  title = {{Engineering morphology of tetrasulfide-incorporated mesoporous silica nanoparticles for enhanced mRNA delivery}},
  author = {Z. Cao and S. Saarela and J. Wang and M. Sivonen and E. Happonen and J. Hepojoki and H. Muramatsu and P. Norbert and V.-P. Lehto and W. Xu},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.763884},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763884v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Engineering morphology of tetrasulfide-incorporated mesoporous silica nanoparticles for enhanced mRNA delivery
AU  - Z. Cao
AU  - S. Saarela
AU  - J. Wang
AU  - M. Sivonen
AU  - E. Happonen
AU  - J. Hepojoki
AU  - H. Muramatsu
AU  - P. Norbert
AU  - V.-P. Lehto
AU  - W. Xu
PY  - 2026
DA  - 2026/11/03
PB  - bioRxiv
DO  - 10.64898/2026.11.03.763884
UR  - https://www.biorxiv.org/content/10.64898/2026.11.03.763884v1
AB  - 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.
ER  -

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