Piezo1 Channel Mediates Mechanically Programmable Drug Delivery to Potentiate Intravesical Chemotherapy

ABSTRACT Intravesical chemotherapy for bladder cancer remains limited by poor efficacy and significant toxicity, imposing profound physical and psychological burdens on patients. While several physical‐assisted approaches comprising hyperthermic intravesical chemotherapy and electromotive drug administration have been investigated to enhance the chemotherapy, but limited in clinical application due to their technical complexity and high costs. Herein, we introduce a simple yet powerful approach: utilizing programmable mechanical pressure as a therapeutic enhancer to establish a mechano‐chemotherapy strategy. We demonstrate that controlled pressure activates the mechanosensitive ion channel Piezo1 in bladder cancer, triggering a calcium ion cascade that transiently and reversibly amplifies mechanosensitivity and membrane permeability. This force‐controlled process obviously enhances intracellular accumulation of standard chemotherapeutics, including Doxorubicin (DOX) and Mitomycin‐C (MMC), leading to significantly increased tumor cell apoptosis. Crucially, mechano‐chemotherapy potently enhances antitumor efficacy while mitigating dose‐limiting mucosal toxicity in orthotopic models. In a word, this work establishes Piezo1‐mediated mechano‐chemotherapy as a readily translatable strategy, transforming mechanical force into a safe and effective tool for optimizing cancer treatment.