Targeted Accumulation of Reactive Acrolein via Nanoparticle-embedded Reverse Temperature Hydrogel for Bladder Cancer Treatment

<b>Rationale:</b> Bladder cancer (BC) frequently recurs after standard surgical resection and is often associated with poor survival outcomes. Local treatment via intravesical instillation of drug <i>in situ</i> is a promising strategy, but its therapeutic efficacy is limited by insufficient retention time and urinary tract obstruction. <b>Methods:</b> We demonstrate that BC exhibits pronounced suppression of acetylpolyamine oxidase (PAOX) compared to normal tissues, as evidenced by multi-platform analysis of patient-derived clinical specimens and GEO database. The PAOX deficiency drives pathological polyamine accumulation in BC cells, uncovering a novel metabolic target with therapeutic implications. Thus, we engineered a novel intravesical instillation system that combines PAOX/targeting peptide-conjugated nanoparticles, synergistically boosting reactive acrolein synthesis while blocking detoxification to induce lethal carbonyl stress, and reverse temperature hydrogels, ensuring liquid dispersion for full bladder coverage during instillation, followed by <i>in situ</i> gelation to prolong nanoparticle retention. <b>Results:</b> <i>In vitro</i> and <i>in vivo</i> results showed that this nanoparticle-embedded hydrogel disrupt redox homeostasis by amplifying lethal carbonyl stress via mitochondrial dysfunction, lipid peroxidation and DNA damage. Remarkably, acrolein binding to GAPDH promotes its nuclear translocation and upregulation of the tumor suppressor protein P53, facilitating apoptosis. <b>Conclusion:</b> This innovative strategy enhances reactive acrolein accumulation by targeting tumor-specific metabolic vulnerabilities, inducing multifaceted cell death for the BC treatment.