Shuo Qiu, Yundi Wu, Ruocan Liu, Huanran Qu, Shiyang Shao, Jianqiang Chen, Xilong Wu
ABSTRACT Reactive oxygen species (ROS)‐based therapies are promising for tumor ablation, but their efficacy is limited by hypoxic microenvironments and poor intratumoral penetration. This study presents a photo/sono/magneto‐responsive ternary heteronanocrystal, BPNS/PCN‐224/Fe 3 O 4 @PVP (BPF), incorporating an S‐scheme heterojunction and Fe‐based nanozyme catalysis. The S‐scheme heterojunction between piezoelectric black phosphorus nanosheets (BPNS) and photosensitizing PCN‐224 enhances ROS generation for synergistic photodynamic therapy (PDT) and ultrasound‐piezocatalytic therapy (UPCT). Superparamagnetic Fe 3 O 4 nanoparticles provide peroxidase‐ and catalase‐like activities, further increasing oxidative stress and reinforcing PDT, UPCT, and chemodynamic therapy. This robust ROS production induces immunogenic cell death, activates immune memory, and elicits systemic antitumor responses. Under ultrasound and magnetic driving, BPF is enriched and actively transported into deep tumor regions, improving intratumoral distribution. The integrated platform achieves efficient ROS‐amplified tumor cell killing, along with near‐infrared fluorescence and T 2 ‐weighted MRI for real‐time treatment guidance. This multifunctional S‐scheme heteronanocrystal offers a promising strategy for penetrative, ROS‐amplified tumor ablation, and enhancing systemic antitumor immune responses.