Selenide-Bridged Redox-Responsive Nanoparticles: A Synergistic Strategy to Overcome p53 Mutation-Mediated Drug Resistance in Gastric Cancer

Selenium deficiency is linked to gastric cancer, and p53 mutant tumors often acquire chemoresistance. To address this, we designed a camptothecin (CPT) dimeric prodrug with a hybrid -S-Se-S- linker (CPT-S-Se-S-CPT). It self-assembles into uniform nanoparticles (SSeSCPT NPs) with dual redox-responsive release triggered by glutathione and reactive oxygen species. Selenium plays dual synergistic roles: it enhances cellular uptake and pharmacokinetics while reducing systemic toxicity; it also acts as a redox-active center to amplify oxidative stress, activating p38/MAPK and unfolded protein response pathways, thereby inducing p53-independent apoptosis and overcoming drug resistance. In vivo, SSeSCPT NPs prolong plasma half-life, achieve efficient tumor accumulation via the EPR effect, and show potent antitumor activity in p53 mutant gastric cancer models. Surface selenium groups recognize Toll-like receptor 4 (TLR4) overexpressed on tumor cells, promoting clathrin/caveolin-mediated endocytosis and bypassing EPR size limitations. This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy. It also reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks. This work provides mechanistic insights and translational directions for precision therapy of p53 mutant gastrointestinal malignancies.