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

Hepatocellular carcinoma (HCC) remains one of the most lethal malignant tumors. Multi-modal therapeutics for HCC have attracted increasing attention. However, designing a nanotherapeutic platform with effective chem-/sono- double-modal HCC therapies is still challenging. Here, we first designed a novel porphyrin-based nanomase (Porzyme) P-Por-Os with nano-sonosensitivity for HCC therapy. Endowed with a large hollow spherical structure of poly porphyrins, which efficiently improved the electron transport capacity of polyporphyrins and exposed the active site of superficial metal atoms, P-Por-Os effectively catalyzed the production of ROS from H2O2. This so-called Chemodynamic Therapy (CDT) was further significantly reinforced by Sonodynamic Therapy (SDT) and achieving this therapeutic ultrasound-controlled anti-tumor effects in HCC. More importantly, we developed an metallothionein-2A (MT2A)-targeted enhancement to reverse the resistance to ROS and suppress cancer progression, which could theoretically be termed Precision Gene Therapy (PGT). Overall, the new therapeutic schedule with the triple-combination of P-Por-Os-based CDT, SDT, and PGT achieved remarkable anti-HCC effectiveness. This study reported an innovative artificial enzyme P-Por-Os with high tumor-killing activity and proposed a new triple-combination with CDT, SDT and PGT treatment strategy for HCC.