Tumor redox heterogeneity-responsive nanoparticles for enhanced antitumor efficacy through combining chemo/chemodynamic therapy

Cancer represents a significant global health threat, and traditional chemotherapy (CT) often encounters limitations in efficacy due to systemic toxic side effects and tumor heterogeneity. The combination of chemodynamic Therapy (CDT) and CT offers a potential solution to overcome the constraints of single-agent therapies. However, many CT/CDT collaborative systems have critical shortcomings, including insufficient active targeting capabilities, depletion of H₂O₂ substrates leading to a reduction in CDT effectiveness, and the heterogeneity of redox within tumor cells, which can result ultimately limit overall efficacy. This study developed a redox heterogeneity-responsive CT/CDT nanoparticle, named HFMD, with the goal of overcoming the limitations associated with traditional CT/CDT nanoparticles. <i>In vitro</i> experiments demonstrated that HFMD exhibits redox-sensitive drug release characteristics and the capacity to generate hydroxyl free radicals. Additionally, HFMD enhances H₂O₂ supply, improves CDT efficiency, and shows significant inhibitory effects on multiple cancer cell lines. <i>In vivo</i> experiments further validated that HFMD possesses excellent tumor-targeting enrichment capabilities and remarkable anti-cancer efficacy, achieving a tumor inhibition rate of approximately 80.1 %. The biological safety assessment indicated that HFMD demonstrates good biocompatibility and successfully mitigates the dose-limiting toxicity associated with free doxorubicin. Overall, this study presents a promising strategy for enhancing anti-cancer efficacy.