Charge Separation‐Engineered Piezoelectric Ultrathin Nanorods Modulate Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Synergistically Piezo‐Thermal‐Immune Therapy

Abstract The tumor microenvironment (TME) is characterized by hypoxia and low immunogenicity, with a dense and rigid extracellular matrix (ECM) that impedes the diffusion of therapeutic agents and immune cells, thereby limiting the efficacy of immunotherapy. To overcome these challenges, an oxygen defect piezoelectric‐photothermal sensitizer, bismuth vanadate nanorod‐supported platinum nanodots (BVP) is developed. The integration of platinum enhances the photothermal effect and improves charge separation efficiency under ultrasound, leading to increased heat generation and the production of reactive oxygen species (ROS) and oxygen. Platinum also catalyzes the conversion of hydrogen peroxide in the TME to oxygen, which serves as both a ROS source and a means to alleviate tumor hypoxia, thereby reversing the immunosuppressive TME. Moreover, the coordination of bismuth ions with glutathione further amplifies cellular oxidative stress. The generated heat and ROS not only denature the collagen in the ECM, facilitating the deeper penetration of BVP into the tumor but also induce immunogenic cell death in tumor cells. Through the “degeneration and penetration” strategy, photoacoustic therapy effectively activates immune cells, inhibiting both tumor growth and metastasis. This study introduces a pioneering approach in the design of antitumor nanomedicines aimed at reversing the immunosuppressive characteristics of the TME.