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While several physical\u2010assisted 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:\u00a0utilizing programmable mechanical pressure as a therapeutic enhancer to establish a mechano\u2010chemotherapy 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\u2010controlled process obviously enhances intracellular accumulation of standard chemotherapeutics, including Doxorubicin (DOX) and Mitomycin\u2010C (MMC), leading to significantly increased tumor cell apoptosis. Crucially, mechano\u2010chemotherapy potently enhances antitumor efficacy while mitigating dose\u2010limiting mucosal toxicity in orthotopic models. In a word, this work establishes Piezo1\u2010mediated mechano\u2010chemotherapy as a readily translatable strategy, transforming mechanical force into a safe and effective tool for optimizing cancer treatment.<\/jats:p>","DOI":"10.1002\/advs.202522936","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:01:52Z","timestamp":1773014512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Piezo1 Channel Mediates Mechanically Programmable Drug Delivery to Potentiate Intravesical Chemotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Minghai","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital, Xi'an Jiaotong University  Xi'an China"},{"name":"Department of Thoracic Surgery Tangdu Hospital Air Force Medical University  Xi'an 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