Harnessing Porous Coordination Cages for Sonodynamic Therapy: Enhanced Efficacy Through Atomic Precision and Immune Activation

Sonodynamic therapy (SDT) has emerged as a promising non-invasive approach for immunotherapy. However, its broad applicability is often limited by the inefficiency of sonosensitizers. Here, we introduce a novel series of porous coordination cages (PCCs) specifically engineered to enhance sonodynamic therapeutic performance for the first time. These PCCs incorporate energy harvesting and conversion components, with variations in bandgap, electrical conductivity, and redox activity. Characterized by atomically precise compositions and well-defined structures, the PCCs enable strategic manipulation of functionalized moieties and metal centers, allowing for precise control over their sonodynamic efficiency. Their small particle size enhances penetration through dense tumor extracellular matrices, significantly improving tumor permeability. Upon ultrasound stimulation, the PCCs exhibit robust sonodynamic effects, resulting in increased reactive oxygen species (ROS) levels in tumor cells, which triggers apoptosis and antigens release. Notably, PCC-1 demonstrates metal-mediated catalytic activity, converting endogenous hydrogen peroxide into additional ROS, synergistically enhancing SDT efficacy and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in dendritic cells. In tumor model, PCCs effectively inhibited tumor growth and activated immune responses both locally and systemically. Collectively, these findings underscore the exceptional sonodynamic-immunotherapeutic potential of PCCs, paving the way for innovative strategies in tumor treatment.