pH-responsive CaCO3 nanoplatform amplifies SDT via calcium overload-ROS loop for deep tumor therapy

Sonodynamic therapy (SDT) for deep-seated tumors is limited by tumor microenvironment (TME) barriers. We developed a hyaluronic acid (HA)-modified mesoporous calcium carbonate nanoplatform (HA/CaCO₃@Ce6) to synergistically enhance calcium overload and SDT. The CD44-targeted nanoplatform demonstrated pH-responsive degradation in acidic TME, resulting in the release of Ca²⁺ and chlorin e6 (Ce6). The released Ca²⁺ induced mitochondrial calcium overload, causing 71% collapse in membrane potential and 1.6-fold increase in reactive oxygen species (ROS) generation, establishing a "Ca²⁺-ROS positive feedback loop." This synergy triggered robust immunogenic cell death (ICD), enhancing CRT exposure by 94.2%, HMGB1 release by 46.2%, and ATP decrease by 74.5%. <i>In vivo</i>, it achieved 90.9% tumor inhibition and 80% 60-day survival rate, alleviated tumor hypoxia, and inhibited tumor proliferation and angiogenesis. This "ion-interference SDT" paradigm overcomes the limitations of SDT through self-amplified ROS cycle and provides an effective strategy for treating deep-seated solid tumor with significant clinical translation potential.