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

• Type of Material: Article
• Authors: Fang-Yi Su, Georgia Institute of Technology; Qingyang Henry Zhao, Georgia Institute of Technology; Shreyas N Dahotre, Georgia Institute of Technology; Lena Gamboa, Georgia Institute of Technology; Swapnil Subhash Bawage, Georgia Institute of Technology; Aaron Silva D Trenkle, Georgia Institute of Technology; Ali Zamat, Georgia Institute of Technology; Hathaichanok Phuengkham, Georgia Institute of Technology; Rafi Ahmed, Emory University; Philip Santangelo, Emory University; Gabe Kwong, Emory University
• Language: English
• Date: 2022-02-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abm7950
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 8
• Issue: 8
• Start Page: eabm7950
• End Page: eabm7950
• Grant/Funding Information: This work was supported by Defense Advanced Research Projects Agency grant HR00111920008 (R.A., P.J.S., and G.A.K.), NIH grant DP2HD091793 (G.A.K.), NIH grant R01CA237210-01 (G.A.K.), NSF grant ECCS-1542174 (G.A.K.), The Burroughs Wellcome Fund, Career Award at the Scientific Interface (G.A.K.), NSF Graduate Research Fellowships Program DGE-1650044 (S.N.D.), NSF Integrative Graduate Education and Research Traineeship DGE-0965945 (S.N.D.), Alfred P. Sloan Foundation (L.G.), NIH GTBioMAT Training Grant 5T32EB006343 (L.G.), NSF Graduate Research Fellowships Program DGE-1451512 (L.G.), NSF Graduate Research Fellowships Program DGE-2039655 (A.D.S.T.), NIH Cell and Tissue Engineering (CTEng) Training Program 5T32GM8433-30 (A.D.S.T.), and Georgia Tech President’s Fellowship (A.Z.)
• Keywords: EPITOPE; Science & Technology; REPERTOIRE; COMPLEXES; RESPONSES; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; PEPTIDE EXCHANGE; Science & Technology - Other Topics; Multidisciplinary Sciences; PROTEIN
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology

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 postinsertion into preformed mRNA lipid nanoparticles. Across different TCR transgenic mouse models (P14, OT-1, and 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 show 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.