Matrix stiffness regulates lipid nanoparticle - mRNA delivery in cell-laden hydrogels

Avathamsa Athirasala, Siddharth Patel, Paula P. Menezes, Jeonghwan Kim, Anthony Tahayeri, Gaurav Sahay, Luiz E. Bertassoni

Research output: Contribution to journalArticlepeer-review

Abstract

mRNA therapeutics have increased in popularity, largely due to the transient and fast nature of protein expression and the low risk of off-target effects. This has increased drastically with the remarkable success of mRNA-based vaccines for COVID-19. Despite advances in lipid nanoparticle (LNP)-based delivery, the mechanisms that regulate efficient endocytic trafficking and translation of mRNA remain poorly understood. Although it is widely acknowledged that the extracellular matrix (ECM) regulates uptake and expression of exogenous nano-complexed genetic material, its specific effects on mRNA delivery and expression have not yet been examined. Here, we demonstrate a critical role for matrix stiffness in modulating both mRNA transfection and expression and uncover distinct mechano-regulatory mechanisms for endocytosis of mRNA through RhoA mediated mTOR signaling and cytoskeletal dynamics. Our findings have implications for effective delivery of therapeutic mRNA to targeted tissues that may be differentially affected by tissue and matrix stiffness.

Original languageEnglish (US)
Article number102550
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume42
DOIs
StatePublished - Jun 2022

Keywords

  • 3D hydrogels
  • LNPs
  • Mechanotransduction
  • RhoA
  • mRNA delivery
  • mTOR

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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