Covalent Interface-Engineered Bone-Targeting Piezoelectric Heterojunction Reprograms Tumor Stress Adaptation and Reverses the Immunosuppressive Microenvironment

Breast cancer bone metastasis remains a major therapeutic challenge due to endoplasmic reticulum stress (ERS)-associated stress adaptation and an immunosuppressive tumor immune microenvironment (TIME). Herein, we report a zoledronic acid (ZOL)-loaded bone-targeted covalent piezoelectric heterojunction nanoplatform (Z@BT-P) for sonopiezo-dynamic therapy (SPDT) and immune remodeling. In this platform, barium titanate (BTO) was covalently integrated with a porphyrinic porous coordination network to form a stable BT-P heterointerface, while ZOL enhanced bone-metastatic lesion enrichment. Compared with physically assembled BT@P, Z@BT-P promoted interfacial charge utilization and strengthened ultrasound (US)-triggered piezoelectric catalysis. Under US irradiation, enhanced charge utilization and Piezo1-associated mechanosensitive Ca2+ signaling jointly amplified reactive oxygen species accumulation and Ca2+ dysregulation, causing dual oxidative/Ca2+ stress. This stress cascade promoted ERS associated with glucose-regulated protein 78 and C/EBP homologous protein, leading to apoptosis and immunogenic cell death. Consequent damage-associated molecular patterns release and ZOL-containing treatment enhanced dendritic cell maturation, drove M1-like macrophage remodeling, and activated antitumor immunity. In a 4T1-luc tibial bone metastasis model, Z@BT-P + US achieved 89.4% ± 4.9% tumor growth inhibition, alleviated osteolytic bone destruction, suppressed distant metastasis, and promoted immune memory. This study establishes a covalent interface-engineered piezoelectric nanoplatform for bone metastasis therapy.