In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles

Su, F.-Y.; Zhao, Q.; Dahotre, S. N.; Gamboa, L.; Bawage, S. S.; Silva Trenkle, A. D.; Zamat, A.; Phuengkham, H.; Ahmed, R.; Santangelo, P.; Kwong, G. A.

doi:10.1101/2021.10.14.464373

bioRxiv · 10.1101/2021.10.14.464373

In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles

Su, F.-Y.·Zhao, Q.·Dahotre, S. N.·Gamboa, L.·Bawage, S. S.·Silva Trenkle, A. D.·Zamat, A.·Phuengkham, H.·Ahmed, R.·Santangelo, P.·Kwong, G. A.

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Abstract

Simultaneous delivery of mRNA to multiple populations of antigen (Ag)-specific CD8+ T cells is challenging given the diversity of peptide epitopes and polymorphism of class I major histocompatibility complexes (MHCI). We developed Ag-presenting nanoparticles (APNs) for mRNA delivery using pMHCI molecules that were refolded with photocleavable peptides to allow rapid ligand exchange by UV light and site-specifically conjugated with a lipid tail for post-insertion into preformed mRNA lipid nanoparticles. Across different TCR transgenic mouse models (P14, OT-1, Pmel), UV-exchanged APNs bound and transfected their cognate Ag-specific CD8+ T cells equivalent to APNs produced using conventionally refolded pMHCI molecules. In mice infected with PR8 influenza, multiplexed delivery of UV-exchanged APNs against three immunodominant epitopes led to ~50% transfection of a VHH mRNA reporter in cognate Ag-specific CD8+ T cells. Our data shows that UV-mediated peptide exchange can be used to rapidly produce APNs for mRNA delivery to multiple populations of Ag-specific T cells in vivo. TeaserLight-induced rapid production of antigen-presenting nanoparticles for mRNA delivery to multiple virus-specific T cell populations.

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Su, F.-Y., Zhao, Q., Dahotre, S. N., Gamboa, L., Bawage, S. S., Silva Trenkle, A. D., Zamat, A., Phuengkham, H., Ahmed, R., Santangelo, P., Kwong, G. A.. 2021-10-15. In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles. https://doi.org/10.1101/2021.10.14.464373

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