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

Abstract 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@CaO 2 ‐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 CaO 2 nanoparticles provide pH‐responsive Ca 2+ /O 2 reservoirs, facilitating CD44‐mediated tumor targeting and PDT‐supportive hypoxia alleviation. Crucially, NIR‐triggered H + generation simultaneously drives dual calcium amplification through accelerated CaO 2 decomposition and potentiated acid‐sensitive ion channel‐mediated Ca 2+ influx, while fueling ICG‐mediated ROS generation via O 2 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.