Hyaluronic acid coated GSH-responsive Mn(III)-pMOF-based nanosonosensitizers for cascade-catalytic enhancement of sonodynamic therapy against hepatocellular carcinoma.

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) has shown potential in treating deep-seated solid tumors owing to its precise targeting capabilities and non-invasive nature. However, the clinical translation of SDT is hindered by conventional sonosensitizers, which fail to effectively penetrate the complex tumor microenvironment and generate sufficient ROS. In this study, we developed a novel nanosonosensitizer system, termed Mn(III)-TCPP@Nic/HA (MTNH). This system was developed by strategically encapsulating the nitric oxide (NO) donor nicorandil within the porous of a Mn(III)-porphyrin-MOF and functionalizing its surface with hyaluronic acid (HA). MTNH effectively accumulates at tumor sites though a combination of the enhanced permeability and retention effect and CD44 receptor-mediated targeting by HA. Under ultrasound irradiation, it exhibits remarkable catalytic capacity for ROS generation. Furthermore, MTNH effectively consumes overexpressed glutathione (GSH) within tumor cells, resulting in in situ GSH depletion (4.3 μmol in 1 h) and NO production (23.9 μM in 24 h). This process further reacts with excess HO to produce •OH radicals, disrupting intracellular redox homeostasis and increasing ROS accumulation. This cascade reaction induced by MTNH significantly enhances SDT efficacy, achieving a remarkable 94.2% inhibition of tumor growth in vivo. This study provides a strategy for achieving efficient SDT against deep-seated tumors.