Hypoxia-Responsive Covalent Organic Framework Nanoplatform for Breast-Cancer-Targeted Cocktail Immunotherapy via...

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-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.