Extracellular vesicle surface display enhances the therapeutic efficacy and safety profile of cancer immunotherapy.

Autor:	Jayasinghe MK; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore., Lay YS; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Liu DXT; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Lee CY; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Gao C; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Yeo BZ; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., How FYX; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Prajogo RC; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Hoang DV; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Le HA; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Pham TT; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Peng B; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Phung CD; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore., Tenen DG; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02138, USA., Le MTN; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore. Electronic address: phcltnm@nus.edu.sg.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jul 20. Date of Electronic Publication: 2024 Jul 20.
DOI:	10.1016/j.ymthe.2024.07.013
Abstrakt:	Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released by cells, can be efficiently engineered via inverse electron demand Diels-Alder (iEDDA)-mediated conjugation to display multiple immunomodulatory ligands on their surface. Display of immunomodulatory ligands on the EV surface conferred substantial enhancements in signaling efficacy, particularly for tumor necrosis factor receptor superfamily (TNFRSF) agonists, where the EV surface display served as an alternative FcγR-independent approach to induce ligand multimerization and efficient receptor crosslinking. EVs displaying a complementary combination of immunotherapeutic ligands were able to shift the tumor immune milieu toward an anti-tumorigenic phenotype and significantly suppress tumor burden and increase survival in multiple models of metastatic cancer to a greater extent than an equivalent dose of free ligands. In summary, we present an EV-based delivery platform for cancer immunotherapeutic ligands that facilitates superior anti-tumor responses at significantly lower doses with fewer side effects than is possible with conventional delivery approaches. Competing Interests: Declaration of interests M.T.N.L. is a scientific co-founder and advisor of Carmine Therapeutics, a start-up company that develops EV-based gene therapy. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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