Delivery of Multifunctional Microspheres via Intravesical Instillation for Bladder Carcinoma: Therapeutic Potential and Mechanistic Insights.

Despite the use of standard intravesical instillation after surgery for non-muscle invasive bladder cancer (NMIBC), current drugs fail to eradicate residual tumor cells and are associated with high recurrence rates. To address this unmet clinical need, we synthesized tumor-targeted poly(1-carboxy-3,3,3-trimethylpropyl methacrylate) (PCTM) microspheres for intravesical delivery using microfluidic and click chemistry. Systematic in vitro and in vivo evaluations demonstrated that the PCTM microspheres exhibit excellent bladder mucosal adhesion, deep tissue penetration, and tumor-specific targeting. Notably, PCTM exerted potent antitumor activity in a variety of bladder cancer cell lines and in orthotopic and ectopic models of urinary bladder cancer, with no serious side effects detected in the peripheral vital organs of mice. Mechanistic studies integrating RNA sequencing, flow cytometry, and western blot analysis showed that PCTM inhibited the proliferation and progression of bladder cancer cells by downregulating CDC42 and HCFC1 and indirectly inhibiting the expression of the cell-cycle protein A1, which subsequently induced S-phase arrest of mitosis. Taken together, these findings suggest that the PCTM microspheres may be a promising intravesical therapeutic agent for bladder cancer tumor eradication, thus providing a transformative strategy to significantly improve the prognosis of patients with NMIBC.