Near Infrared‐Activatable Nanomodulator Enabling Self‐Amplifying Calcium Overload and Oxidative Stress for Precision Cancer Therapy

Calcium interference therapy (CIT) is a promising cancer therapeutic strategy, but its efficacy is limited by intrinsic cellular calcium regulation. To address this limitation, herein, a near-infrared (NIR)-responsive nanoplatform, UC@COFs@CaO₂-HA/PAG/ICG (UCCPI), integrating dual-amplified CIT with photodynamic therapy (PDT) is engineered to enhance therapeutic outcomes. The core-shell upconversion nanoparticle-engineered covalent organic framework nanocomposites (UC@COFs) serve as both pH-dependent fluorescent probes for cancer cell imaging and drug-delivery carriers co-loading photoacid generators (PAG) and photosensitizer indocyanine green (ICG). The embedded upconversion nanoparticles (UCNPs) convert 980 nm NIR light into visible emissions, enabling spatiotemporal PAG activation for localized H⁺ release and overcoming UV/visible light depth limitations. Surface-modified hyaluronic acid (HA)-functionalized CaO₂ nanoparticles provide pH-responsive Ca²⁺/O₂ reservoirs, facilitating CD44-mediated tumor targeting and PDT-supportive hypoxia alleviation. Crucially, NIR-triggered H⁺ generation simultaneously drives dual calcium amplification through accelerated CaO₂ decomposition and potentiated acid-sensitive ion channel-mediated Ca²⁺ influx, while fueling ICG-mediated ROS generation via O₂ supply for PDT. These interconnected processes synergistically amplify mitochondrial calcium overload and oxidative damage. Collectively, UCCPI demonstrates excellent biocompatibility, precise tumor targeting, and self-amplifying therapeutic effects both in vitro and in vivo. This work presents a tumor microenvironment-targeted strategy to potentiate mitochondrial dysfunction through integrated ion interference and oxidative stress mechanisms.