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Abstract 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‐NH 2 (UiO) to form UiO@Au‐Pd islands (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‐Pd islands @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.
Huang et al. (Fri,) studied this question.