Hypoxia‐Responsive Covalent Organic Framework Nanoplatform for Breast‐Cancer‐Targeted Cocktail Immunotherapy via Triple Therapeutic Switch Mechanisms

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 21; no. 7; pp. e2407553 - n/a
• Main Authors: Huang, Guoqin, Zhang, Lianying, Feng, Jiahao, Wu, Dan, Wu, Libo, Pan, Weilun, Jiang, Yu, Chen, Ming, Chen, Jinxiang, Shui, Pixian
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.02.2025
• Subjects: Animals; Bimetals; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer; Catalase; Cell Line, Tumor; Chemotherapy; cocktail therapy; Core-shell structure; Drug delivery systems; Encapsulation; Female; Heat shock proteins; Humans; Hyaluronic acid; Hypoxia; hypoxia‐responsive COF; Immunotherapy - methods; in situ encapsulation; In vivo methods and tests; Lymphocytes; Metal-Organic Frameworks - chemistry; Mice; Nanoparticles - chemistry; NIR‐II mild‐PTT; Oxygen; Palladium; Peroxidase; Reactive Oxygen Species - metabolism; triple therapeutic response; Tumor Microenvironment - drug effects; Tumors; Xanthones - chemistry; Xanthones - pharmacology; Xanthones - therapeutic use; triple therapeutic response; cocktail therapy; in situ encapsulation; hypoxia‐responsive COF; NIR‐II mild‐PTT
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202407553

Covalent organic frameworks (COFs), known for their exceptional in situ encapsulation and precise release capabilities, are emerging as pioneering drug delivery systems. This study introduces a hypoxia‐responsive COF designed to encapsulate the chemotherapy drug gambogic acid (GA) in situ. Bimetallic gold‐palladium islands were grown on UiO‐66‐NH2 (UiO) to form UiO@Au‐Pdislands (UAPi), which were encapsulated with GA through COF membrane formation, resulting in a core‐shell structure (UAPiGC). Further modification with hyaluronic acid (HA) created UiO@Au‐Pdislands@GA‐COF@HA (UAPiGCH) for enhanced tumor targeting. In the hypoxic tumor microenvironment, the COF collapses, releasing GA and UAPi, initiating a triple therapeutic response: nanozyme‐catalyzed therapy, near‐infrared II (NIR‐II) mild photothermal therapy (mild‐PTT), and chemotherapy. UAPi exhibits catalase (CAT)‐like and peroxidase (POD)‐like activities, generating oxygen to alleviate hypoxia and reactive oxygen species (ROS) for tumor destruction. GA acts as a chemotherapeutic agent and inhibits heat shock protein 90 (HSP90), enhancing photothermal sensitivity. In vitro and in vivo studies confirm UAPiGCH’s ability to induce pyroptosis, stimulate dendritic cell maturation, and boost T cell infiltration, demonstrating its potential as a precise therapeutic nanoplatform. This strategy integrates multiple therapies into a hypoxia‐responsive system, offering promising applications in cancer treatment. UAPiGCH, a hypoxia‐responsive nanocomposite, integrates chemotherapy, nanozyme‐catalyzed therapy, and NIR‐II mild‐photothermal therapy. Selectively targeting tumors, it induces pyroptosis, dendritic cell maturation, and T cell infiltration. In vitro and in vivo studies confirm its efficacy and safety, positioning it as a promising platform for cancer therapy.