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

• 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
• Journal Title: SCIENCE ADVANCES
• Volume: Volume 8, Number 8
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE | 2022-02-01, Pages eabm7950-eabm7950
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1126/sciadv.abm7950
• Subjects: Engineering, Biomedical; Health Sciences, Immunology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; PEPTIDE EXCHANGE; REPERTOIRE; COMPLEXES; RESPONSES; PROTEIN; EPITOPE

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.