Targeting ERCC2 with\nsiRNA Self-Assembled Nanoparticles\nto Enhance the Cisplatin Response in Bladder Cancer

Cisplatin resistance in bladder cancer significantly\nhinders further\nimprovement in clinical efficacy. This resistance can be mediated\nthrough nucleic acid repair pathways to counteract the damage of cisplatin\nto the tumor genome, in which Excision Repair Cross-Complementation\nGroup 2 (ERCC2) plays an indispensable role as a key factor. Currently,\nthere is a lack of effective therapeutic strategies targeting ERCC2\nto intervene in bladder cancer resistance. Herein, we scrutinized\nhigh-frequency mutational genes in bladder cancer and found that mutations\nin ERCC2 precipitated diminished expression levels and functional\nimpairments, correlating with improved patient prognosis. Subsequent <i>in vitro</i> knockdown experiments confirmed that reducing ERCC2\nexpression significantly increased the sensitivity of bladder cancer\ncells to cisplatin. To combat drug resistance by targeting ERCC2,\nwe employed rolling circle transcription to create a carrier for the\nhigh-capacity, tumor-targeted delivery of ERCC2 small interfering\nRNA (siRNA). This carrier was compacted from micron scale to approximately\n150 nm using polyethylenimine and further modified with an aptamer\nto enhance tumor targeting and knockdown efficacy. The uptake of the\ntargeted carrier by tumor cells increased by 42.5%. When combined\nwith cisplatin, it substantially augmented the cytotoxic impact on\nresistant bladder cancer cell lines. Moreover, in resistant mouse\ntumor models, this effective siRNA delivery system improved chemotherapeutic\noutcomes with minimal toxicity. Therefore, this delivery system holds\npromise for RNA interference-based strategies in overcoming chemotherapy\nresistance in bladder cancer treatment.