Localized in-situ nanomedicine synthesis enables copper-mediated cuproptosis for effective bladder cancer therapy.

Nanomedicine based approaches offer new prospects for cancer treatment by enabling localized delivery, improved tissue retention, and microenvironment response therapeutic activation. Bladder cancer remains challenging due to high recurrence rate and the limited effectiveness of conventional intravesical therapies largely resulting from insufficient tissue penetration and short drug residence time, especially under fluid washouts (urination). This study aims to develop a locally administered nanomedicine platform that exploits the anatomical and biochemical feature of bladder for enhanced therapeutic efficacy. We developed a copper integrated polydopamine based nanomedicine (uDHC) system synthesized in-situ within the bladder cavity via metal-assisted rapid polymerization. The resulting nanomedicine exhibit strong adhesion to bladder mucosa, enabling prolonged retention. Incorporation of urease allows utilization of endogenous urea present in urine generating localized physiochemical gradients that enhance nanomedicine penetration into tumor tissue. The sustained copper release disrupts mitochondrial copper homeostasis and induces cuproptosis by modulating key mitochondrial metabolic regulators. In parallel, the polydopamine matrix enables efficient near-infrared photothermal conversion amplifying tumor cell damage and promoting immunogenic cell death. In-vitro studies demonstrate cytotoxicity towards the bladder cancer cells with minimal effects on normal uroepithelial cells. In an orthotopic bladder cancer mouse model, intravesical administration of this nanomedicine system significantly suppresses tumor growth, particularly when combined with near-infrared irradiation. Overall, this multifunctional nanomedicine platform integrates localized delivery, microenvironment response activation, enhanced tissue penetration, and synergistic cuproptosis and photothermal effects, addressing key limitation of current intravesical therapies and supporting the translational potential of in-situ synthesized nanomedicine for localized bladder cancer treatment.