Acidity-Responsive Fe-PDA@CaCO₃ Nanoparticles for Photothermal-Enhanced Calcium-Overload- and Reactive-Oxygen-Species-Mediated Tumor Therapy

Calcium-overload-mediated tumor therapy has received considerable interest in oncology. However, its efficacy has been proven to be inadequate due to insufficient calcium ion concentration at the tumor site coupled with challenges in facilitating efficient calcium uptake by tumors, leading to unsatisfactory therapeutic outcomes. In the present study, calcium carbonate nanoshell mineralized ferric polydopamine nanoparticles (Fe-PDA@CaCO 3 NPs) were prepared for achieving Ca 2+ -overload-mediated tumor therapy. Upon entering the tumor site, the pH-responsive CaCO 3 layer, acting as a “Ca 2+ storage pool”, rapidly degraded and released high quantities of free Ca 2+ within the weakly acidic environment. The Fe-PDA core, with its excellent photothermal conversion properties, could significantly increase the temperature upon exposure to near-infrared (NIR) light irradiation, thereby activating the TRPV1 channel and leading to a large influx of released Ca 2+ into the cytoplasm. Furthermore, the exposed Fe-PDA core could react with the tumor-overexpressed hydrogen peroxide (H 2 O 2 ) to efficiently produce hydroxyl radicals (•OH), significantly increasing intracellular reactive oxygen species (ROS) levels and thus inhibiting the activity of the Ca 2+ efflux pump, resulting in a high intracellular Ca 2+ concentration. Ultimately, the increase in calcium/ROS levels could disrupt mitochondrial homeostasis and activate the apoptosis pathway. The current work presents a promising approach for tumor therapy using photothermal-enhanced calcium-overload-mediated ion interference therapy and chemodynamic therapy.