Hierarchically engineered covalent organic framework nanoplatforms enable synergistic photothermal-photodynamic-chemotherapeutic breast cancer therapy.

The therapeutic efficacy of phototherapy-based cancer nanomedicines is often limited by insufficient integration of multiple treatment modalities and poor spatiotemporal control over drug release. Herein, we report a hierarchically engineered, pH-responsive covalent organic framework (COF)-based nanoplatform that unifies photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy within a single structurally coherent system. An imine-linked COF (TAPB-DMTP-COF) is employed as a robust and porous scaffold to enable the in situ growth of photothermal CuS nanodomains, ensuring intimate interfacial coupling and efficient near-infrared (808 nm) light-to-heat conversion. Subsequent conformal encapsulation with an acid-labile ZIF-8 shell affords a multifunctional outer layer that simultaneously serves as a high-capacity reservoir for the photosensitizer indocyanine green (ICG) and a tumor-microenvironment-responsive gatekeeper for controlled drug release. The broad-spectrum chemotherapeutic agent doxorubicin (DOX) is incorporated into the hierarchical architecture, while hyaluronic acid functionalization enhances colloidal stability and tumor targeting. Under dual-wavelength laser irradiation (655/808 nm), the nanoplatform exhibits synergistically amplified reactive oxygen species generation, rapid photothermal heating, and pH-accelerated chemotherapy, resulting in pronounced cancer cell ablation. Systematic in vitro and in vivo studies demonstrate minimal dark cytotoxicity toward normal cells, efficient tumor accumulation, and remarkably enhanced antitumor efficacy under combined photodynamic-photothermal activation, with no observable systemic toxicity. This work establishes a COF-enabled design paradigm for constructing hierarchically integrated, stimulus-responsive nanotherapeutics and highlights the promise of reticular materials as programmable platforms for precision multimodal cancer therapy.