Dual-Physical-Field Nanocatalysis: Injectable Hydrogel Enables Piezo-Photothermal Synergy for Breast Cancer Therapy.

Piezocatalytic therapy (PCT) harnesses mechanical energy to generate tumor-lethal reactive oxygen species (ROS), but its efficacy is limited by rapid electron-hole recombination and poor intratumoral retention. To overcome these limitations, we engineered heterostructured BiOCl@CuO nanosheets embedded in an injectable, conductive, thermosensitive hydrogel composed of Pluronic F127 (F127) and reduced graphene oxide (rGO), with rGO specifically enhancing the hydrogel's mechanical strength and conductivity, for the combinational treatment of breast cancer. Under ultrasound (US) stimulation, BiOCl@CuO establishes a strong interfacial electric field that enhances charge separation and accelerates the generation of ROS. In addition, near-infrared (NIR) irradiation activates BiOCl@CuO to convert light into heat, elevating intratumoral temperature and further amplifying ROS-mediated cytotoxicity while enabling photothermal therapy (PTT). The integrated BiOCl@CuO/F127@rGO hydrogel exhibits rapid sol-gel transition at physiological temperature, robust tissue adhesion, and sustained local retention. In vitro, the synergistic therapy induced marked ROS bursts and achieved 60% breast cancer cell ablation at 50 µg/mL with less than 10% toxicity to normal cells. In vivo, orthotopic breast tumors treated with US+NIR showed 90% regression, reduced proliferation and angiogenesis, activation of apoptotic and immunogenic cell death pathways, and favorable biocompatibility. Critically, the regimen triggered robust local immune activation, increasing intratumoral CD8 T cell infiltration by 2.7-fold and IFN-γ secretion by 5-fold while upregulating DC maturation markers (CD80/CD86+) by 3-fold. This work establishes a precise, minimally invasive strategy that couples piezocatalysis with photothermal conversion for effective breast cancer therapy.