1. Academic Validation
  2. Catalytical nano-immunocomplexes for remote-controlled sono-metabolic checkpoint trimodal cancer therapy

Catalytical nano-immunocomplexes for remote-controlled sono-metabolic checkpoint trimodal cancer therapy

  • Nat Commun. 2022 Jun 16;13(1):3468. doi: 10.1038/s41467-022-31044-6.
Chi Zhang 1 Jingsheng Huang 1 Ziling Zeng 1 Shasha He 1 Penghui Cheng 1 Jingchao Li 1 Kanyi Pu 2 3 4
Affiliations

Affiliations

  • 1 School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore, Singapore.
  • 2 School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, 637457, Singapore, Singapore. kypu@ntu.edu.sg.
  • 3 School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, 637371, Singapore, Singapore. kypu@ntu.edu.sg.
  • 4 Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, 636921, Singapore, Singapore. kypu@ntu.edu.sg.
Abstract

Checkpoint immunotherapies have been combined with other therapeutic modalities to increase patient response rate and improve therapeutic outcome, which however exacerbates immune-related adverse events and requires to be carefully implemented in a narrowed therapeutic window. Strategies for precisely controlled combinational Cancer Immunotherapy can tackle this issue but remain lacking. We herein report a catalytical nano-immunocomplex for precise and persistent sono-metabolic checkpoint trimodal Cancer therapy, whose full activities are only triggered by sono-irradiation in tumor microenvironment (TME). This nano-immunocomplex comprises three FDA-approved components, wherein checkpoint blockade inhibitor (anti-programmed death-ligand 1 antibody), immunometabolic reprogramming Enzyme (Adenosine Deaminase, ADA), and sonosensitizer (hematoporphyrin) are covalently immobilized into one entity via acid-cleavable and singlet oxygen-activatable linkers. Thus, the activities of the nano-immunocomplex are initially silenced, and only under sono-irradiation in the acidic TME, the sonodynamic, checkpoint blockade, and immunometabolic reprogramming activities are remotely awakened. Due to the enzymatic conversion of adenosine to inosine by ADA, the nano-immunocomplex can reduce levels of intratumoral adenosine and inhibit A2A/A2B adenosine receptors-adenosinergic signaling, leading to efficient activation of immune effector cells and inhibition of immune suppressor cells in vivo. Thus, this study presents a generic and translatable nanoplatform towards precision combinational Cancer Immunotherapy.

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