Synergistic Sonodynamic/Chemotherapeutic Suppression of Hepatocellular Carcinoma by Targeted Biodegradable Mesoporous Nanosonosensitizers

<jats:title>Abstract</jats:title><jats:p>Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide featured with the poor prognosis and high mortality in affected patients. Given its insensitivity to conventional systemic chemotherapy, the development of novel modalities for HCC management is highly urgent. Sonodynamic therapy (SDT) has gained considerable momentum in cancer therapy. Especially, through synergistic SDT/chemotherapy, SDT would enhance the chemotherapeutic process on inhibiting tumor growth, which holds great potential on combating HCC. In this work, we report on the design/fabrication of targeted biodegradable nanosonosensitizers based on hollow mesoporous organosilica nanoparticles (HMONs), followed by pore‐engineering including covalent anchoring of protoporphyrin (PpIX, HMONs‐PpIX) and conjugation of arginine‐glycine‐aspartic acid in order to specifically targeting HCC cells. Such nanosonosensitizers provide efficient loading and controllable stimuli‐responsive release of chemotherapeutic agents for HCC‐targeting chemotherapy, thus promoting an enhancing chemotherapeutic process via the unique sonotoxicity under ultrasound irradiation. The HMONs matrix with biologically active organic groups in the framework (disulfide bond) are endowed with intrinsic tumor microenvironment‐responsive biodegradability and improved biocompatibility/biosafety. In particular, a synergistic inhibition effect of drug‐loaded HMONs‐PpIX‐arginine‐glycine‐aspartic acid on HCC growth has been systematically demonstrated both in vitro and in vivo (84.7% inhibition rate), which brings insights and meets the versatile therapeutic requirements for HCC management.</jats:p>