title: Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells.
abstract: Cytotoxic T-Lymphocytes (CTLs) kill pathogen-infected or transformed cells following interaction of their T-cell receptors (TCRs) with foreign (e.g. virus-derived) peptides bound to MHC-I molecules on the target cell. TCR binding triggers CTLs to secrete perforin, which forms pores in the target cell membrane, promoting target death. Here, we show that by conjugating drug-loaded lipid nanoparticles to the surface of CTLs, their lytic machinery can be co-opted to lyse the cell-bound drug carrier, providing triggered release of drug cargo upon target cell recognition. Protein encapsulated in T-cell-bound nanoparticles was released following culture of CTLs with target cells in an antigen dose- and perforin-dependent manner and coincided with target cell lysis. Using this approach, we demonstrate the capacity of HIV-specific CTLs to deliver an immunotherapeutic agent to an anatomical site of viral replication. This strategy provides a novel means to couple drug delivery to the action of therapeutic cells in vivo.
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Dept of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, MGH, Boston, MA, USA.
authors.forename: Vlad
authors.initials: V
authors.lastname: Vrbanac
authors.affiliation: Astronomy Dept., Columbia University, New York, NY, USA.
authors.forename: Shy
authors.initials: S
authors.lastname: Genel
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Dept. of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA; Dept. of Biological Engineering, MIT, Cambridge, MA, USA; Dept. of Materials Science & Engineering, MIT, Cambridge, MA, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Dept. of Biological Engineering, MIT, Cambridge, MA, USA; Dept. of Materials Science & Engineering, MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: djirvine@mit.edu.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D001324:Autoantigens / Q000276:immunology*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*
chemical_list: D019380:Anti-HIV Agents; D001324:Autoantigens; D003692:Delayed-Action Preparations; D053769:Nanocapsules
keywords: Cytotoxic T lymphocytes; Drug delivery; Immunotherapy; Lipid nanocapsules; T-pharmacyte