Synergistic\nUltrasound-Activable Artificial Enzyme\nand Precision Gene Therapy to Suppress Redox Homeostasis and Malignant\nPhenotypes for Controllably Combating Hepatocellular Carcinoma

Hepatocellular\ncarcinoma (HCC) remains one of the most lethal malignant\ntumors. Multimodal therapeutics with synergistic effects for treating\nHCC have attracted increasing attention, for instance, designing biocompatible\nporphyrin-based nanomedicines for enzyme-mimetic and ultrasound (US)-activable\nreactive oxygen species (ROS) generation. Despite the promise, the\nlandscape of such advancements remains sparse. Here, we propose the\nde novo design of a π-conjugated, osmium (Os)-coordinated polyporphyrin\n(P-Por-Os) nanovesicle to serve as an ultrasound-activable artificial\nenzyme for synergistic therapies to suppress redox homeostasis and\nmalignant phenotypes for controllably combating HCC. Our findings\nreveal that the P-Por-Os with US showed superior, multifaceted, and\ncontrollable ROS-generating activities. This system not only subverts\nthe redox balance within HCC cells but also achieves precise and controlled\ntumor ablation at remarkably low concentrations, as evidenced across\ncellular assays and animal models. In the liver orthotopic model,\nUS not only activates the artificial enzyme to catalyze ROS but also\nfacilitates remote-controlled ablation of HCC through precise US positioning.\nMoreover, the P-Por-Os + US can assist the precision gene therapy\nby knocking down the ROS resistance factor, MT2A, and down-regulating\nits downstream oncogene IGFBP2 to attenuate ROS resistance, proliferation,\nand migration of HCC efficiently. We suggest that the design of this\nultrasound-activable artificial enzyme presents a promising avenue\nfor the engineering of innovative tumoricidal materials, offering\na synergistic therapeutic approach with high biosecurity for HCC treatment.