Mechanoregulatory Cholesterol Oxidase‐Functionalized Nanoscale Metal–Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 19; no. 52; pp. e2305440 - n/a
• Main Authors: Zhen, Wenyao, Luo, Taokun, Wang, Zitong, Jiang, Xiaomin, Yuan, Eric, Weichselbaum, Ralph R., Lin, Wenbin
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.12.2023
• Subjects: Calcium ions; Cancer; Cell membranes; Cholesterol; cholesterol depletion; Cholesterol Oxidase; Depletion; Fragility; Humans; immune checkpoints; Immune system; Lipids; Lymphocytes; Mechanical properties; Metal-organic frameworks; Metal-Organic Frameworks - pharmacology; nanoscale metal–organic frameworks; Neoplasms; Oxidative stress; Pyroptosis; T-Lymphocytes; Tumor Microenvironment; tumor microenvironment remodeling; Tumors; pyroptosis; nanoscale metal-organic frameworks; tumor microenvironment remodeling; cholesterol depletion; immune checkpoints
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202305440

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD‐functionalized nanoscale metal–organic framework, Hf‐TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf‐TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase‐1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf‐TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf‐TBP, Hf‐TBP/COD improves anti‐tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple‐negative breast cancer model and a colon cancer model, respectively. In this paper, a cholesterol oxidase (COD)‐functionalized metal–organic framework, Hf‐TBP/COD, is designed to simultaneously increase plasma membrane mechanical tension and downregulate the tolerance of cancer cells to reactive oxygen species and pyroptosis, leading to enhanced immunogenic cell death of cancer cells and reinvigorated T cells by inhibiting multiple immune checkpoints for potent antitumor immune responses.