Metal–organic nanostructures based on sono/chemo-nanodynamic synergy of TixOy/Ru reaction units: for ultrasound-induced dynamic cancer therapy

Abstract Sonodynamic therapy (SDT) has demonstrated significant clinical potential in malignant tumor treatment due to its deep tissue penetration and spatiotemporal controllability. Its core mechanism relies on ultrasound-activated sonosensitizers to generate reactive oxygen species (ROS), thereby inducing tumor cell apoptosis. However, conventional sonosensitizers face limitations in ROS yield and tumor-targeting efficiency. In this study, we innovatively designed a multifunctional metal-organic nanosheet (TiZrRu-MON) by hydrothermal coordination of [Ru(bpy)3]2+ photosensitizing units with TiZr-O clusters, while incorporating Fe3+ to construct a cascade catalytic system. Experimental results demonstrated that: (1) Fe3+ lattice doping significantly enhanced charge carrier mobility and ultrasound-triggered 1O2 quantum yield via the formation charge transfer channels; (2) The acidic tumor microenvironment activated Fe3+-mediated Fenton reactions, establishing a positive feedback loop with SDT to synergistically amplify ROS generation; (3) Hyaluronic acid functionalization improved nanosheet internalization in HepG2 tumor cells through CD44 receptor-mediated endocytosis. Remarkably, ultrasound irradiation induced substantial oxidative stress and immunogenic cell death, promoting the release of damage-associated molecular patterns (DAMPs), which elevated the maturation rate of tumor-infiltrating dendritic cells (DCs) and significantly increased the proportion of CD8+ T cells. In a mouse subcutaneous tumor model, the system achieved effective tumor suppression with manageable systemic toxicity. This work proposes a metal-ligand coordination strategy to advance the development of high-performance sonosensitizers and immunomodulatory antitumor technologies.