Targeting ERCC2 with siRNA Self-Assembled Nanoparticles to Enhance the Cisplatin Response in Bladder Cancer

Cisplatin resistance in bladder cancer significantly hinders further improvement in clinical efficacy. This resistance can be mediated through nucleic acid repair pathways to counteract the damage of cisplatin to the tumor genome, in which Excision Repair Cross-Complementation Group 2 (ERCC2) plays an indispensable role as a key factor. Currently, there is a lack of effective therapeutic strategies targeting ERCC2 to intervene in bladder cancer resistance. Herein, we scrutinized high-frequency mutational genes in bladder cancer and found that mutations in ERCC2 precipitated diminished expression levels and functional impairments, correlating with improved patient prognosis. Subsequent in vitro knockdown experiments confirmed that reducing ERCC2 expression significantly increased the sensitivity of bladder cancer cells to cisplatin. To combat drug resistance by targeting ERCC2, we employed rolling circle transcription to create a carrier for the high-capacity, tumor-targeted delivery of ERCC2 small interfering RNA (siRNA). This carrier was compacted from micron scale to approximately 150 nm using polyethylenimine and further modified with an aptamer to enhance tumor targeting and knockdown efficacy. The uptake of the targeted carrier by tumor cells increased by 42.5%. When combined with cisplatin, it substantially augmented the cytotoxic impact on resistant bladder cancer cell lines. Moreover, in resistant mouse tumor models, this effective siRNA delivery system improved chemotherapeutic outcomes with minimal toxicity. Therefore, this delivery system holds promise for RNA interference-based strategies in overcoming chemotherapy resistance in bladder cancer treatment.