Dual-Responsive Nanozyme Reactor Based on Hollow MnO2 on Upconversion Nanoparticles for Targeted Hepatocellular Carcinoma Therapy

Abstract Hepatocellular carcinoma (HCC) remains a significant therapeutic challenge due to multiple bottlenecks, including low early diagnosis rates, rapid disease progression, and limited efficacy of monotherapy. Against this backdrop, multimodal integrated treatment has emerged as a core solution. Here, we reported a tumor-microenvironment (TME)-activatable “nano-cocktail” (UMDCAc) that synchronizes photodynamic (PDT), chemodynamic (CDT), and starvation (ST) therapies for synergistic HCC eradication. UMDCAc was engineered by growing hollow MnO2 (HMnO2) on upconversion nanoparticles (UCNPs), coloading dihydroartemisinin (DHA) and the photosensitizer chlorin e6 (Ce6), and in situ anchoring ultrasmall gold nanoparticles (AuNPs) that mimic glucose oxidase (GOx). Surface modification with cyclic RGD peptides enabled active targeting of αvβ3 integrin. The targeting strategy synergizes with near-infrared (NIR) light-activated catalysis to enhance therapeutic efficacy. Invitro and invivo data demonstrate that UMDCAc achieves tumor suppression through synergistically amplified reactive oxygen species (ROS) generation, hypoxia relief, and targeted delivery, while maintaining favorable biocompatibility and safety and exhibiting superior efficacy over monotherapy. The synergistically generated ROS compromise cellular antioxidant defenses, induce lipid peroxidation, and double the apoptosis rate, thereby producing effective antitumor effects. Therefore, this innovative multimodal strategy offers opportunities for collaborative cancer therapy.