A pH-responsive nanoplatform enhancing tumor therapy via calcium overload-induced oxidative stress to potentiate phototherapy and chemotherapy

Abstract

The specific tumor microenvironment (TME) and the ability of tumor cells to evade drug therapy pose challenges to the efficacy of single monotherapies. Herein, a multifunctional calcium carbonate-based nanoprobe (Fe₃O₄/CaCO₃-CSL/ICG) was synthesized using a simple one-step method. This nanoprobe is designed to respond specifically to the acidic TME, where the calcium carbonate shell dissolves, releasing therapeutic agents. It combines three therapeutic modalities: phototherapy, chemotherapy, and ion interference therapy. In cell experiments, it was confirmed that after entering tumor cells, the acidic intracellular environment triggered the release of calcium ions from the nanoprobe, leading to mitochondrial calcium ion overload. The loaded indocyanine green (ICG) produced photothermal and photodynamic effects under near-infrared laser irradiation. The reactive oxygen species (ROS) generated by photodynamic therapy further amplify oxidative stress caused by mitochondrial calcium overload. Additionally, celastrol (CSL) enhanced calcium ion-induced mitochondrial calcium death. Differential gene expression analysis further supported the combined therapeutic effect of Fe₃O₄/CaCO₃-CSL/ICG, indicating the regulation of genes related to calcium regulation, oxidative stress and apoptosis. In summary, we developed a responsive nanoplatform with pH-triggered degradation and controlled drug release, which enhances tumor suppression by inducing mitochondrial apoptosis through calcium overload and ROS accumulation, in combination with chemotherapy and phototherapy. This work presents a promising nanotherapeutic strategy for tumor treatment.