Urease-Powered Nanomotors for Enhanced Mucosal and Tumor Penetration To Augment Sonodynamic Therapy in Bladder Cancer

Sonodynamic therapy (SDT) represents a promising minimally invasive approach for treating bladder cancer, however, its efficacy following intravesical instillation is substantially compromised by the glycosaminoglycan-rich mucosal barrier and the cyclic voiding process of the bladder. To address these limitations, nanomotors coloaded with enzyme and sonosensitizer were engineered to enhance self-propelled tissue penetration and prolong retention of SDT for bladder cancer. Herein, urine-derived exosomes (EXO) were isolated using density gradient ultracentrifugation and subsequently engineered into EXO@UT nanovesicles (NVs) via electroporation-mediated coencapsulation of urease and tetrakis (4-carboxyphenyl) porphyrin. The NVs catalyze the decomposition of urea within the bladder to generate carbon dioxide and ammonia, thereby propelling their migration toward the bladder mucosa and circumventing washout during micturition as well as enhanced retention within tumor. Following intravesical administration in mice bearing bladder cancer, the NVs with self-propulsion demonstrated significantly enhanced infiltration into mucosal tissues and improved drug accumulation at the tumor site, compared to static counterpart which remained largely localized on the mucosal surface. The self-propelled NVs for SDT activated by low-intensity ultrasound irradiation demonstrated significantly stronger tumor growth suppression and extended animal survival compared to those exposed to external near-infrared illumination. Thus, this study presents a robust therapeutic platform based on self-propelled NVs that effectively overcome mucosal barriers and potentiate SDT, offering a promising strategy for enhanced treatment of bladder cancer.