Synergistic Ultrasound-Activable Artificial Enzyme and Precision Gene Therapy to Suppress Redox Homeostasis and Malignant Phenotypes for Controllably Combating Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains one of the most lethal malignant tumors. Multimodal therapeutics with synergistic effects for treating HCC have attracted increasing attention, for instance, designing biocompatible porphyrin-based nanomedicines for enzyme-mimetic and ultrasound (US)-activable reactive oxygen species (ROS) generation. Despite the promise, the landscape of such advancements remains sparse. Here, we propose the de novo design of a π-conjugated, osmium (Os)-coordinated polyporphyrin (P-Por-Os) nanovesicle to serve as an ultrasound-activable artificial enzyme for synergistic therapies to suppress redox homeostasis and malignant phenotypes for controllably combating HCC. Our findings reveal that the P-Por-Os with US showed superior, multifaceted, and controllable ROS-generating activities. This system not only subverts the redox balance within HCC cells but also achieves precise and controlled tumor ablation at remarkably low concentrations, as evidenced across cellular assays and animal models. In the liver orthotopic model, US not only activates the artificial enzyme to catalyze ROS but also facilitates remote-controlled ablation of HCC through precise US positioning. Moreover, the P-Por-Os + US can assist the precision gene therapy by knocking down the ROS resistance factor, MT2A, and down-regulating its downstream oncogene IGFBP2 to attenuate ROS resistance, proliferation, and migration of HCC efficiently. We suggest that the design of this ultrasound-activable artificial enzyme presents a promising avenue for the engineering of innovative tumoricidal materials, offering a synergistic therapeutic approach with high biosecurity for HCC treatment.