Background Fenton reaction-based chemodynamic therapy (CDT) is regarded as a highly tumor-specific treatment modality due to its intrinsic tumor microenvironment (TME)-specific targeting properties, such as high amounts of lactic acid and H2O2. To improve the therapeutic efficacy of CDT, in this study, a self-tracking and external stimuli-responsive Fenton nanoreactor was accompanied by type I photodynamic therapy. Results A cisplatin-containing H2O2 self-supplying heterogeneous Fenton nanocatalyst (CaO2.CDDP@Fe3O4) was constructed, and it was accompanied by graphitic carbon nitride (g-C3N4) nanosheets as a photosensitizer. The hybrid nanocomposite was decorated with ascorbic acid, which improved the tumor-targeting capabilities of the final construct (CCFCA). Besides the generation of hydroxyl radicals (•OH) by metal-based Fenton nanocatalyst (CaO2.CDDP@Fe3O4), g-C3N4-driven nonmetal-based Fenton reaction translated external energy into extremely lethal free radicals within the tumor cells through oxygen-independent type-I PDT. According to 2D and 3D cell culture experiments, CCFCA demonstrated cancer cell selectivity and a high cellular uptake efficiency under a static magnetic field (SMF) and visible light irradiation. Further investigations showed that CCFCA suppressed the antioxidant system and altered the mitochondrial membrane potential and consequently caspase activity, causing apoptosis in cancer cells. The enhanced tumor-inhibitory capability of the nanocomposites was shown by the increased anti-tumor activity of CCFCA in treated mice under SMF and light irradiation as compared to those treated with the free drug. Moreover, no deleterious effects on normal tissues and blood cells were observed in CCFCA-treated mice. Conclusion Based on the results obtained, dual Fenton reactions were provided in a simple platform (CCFCA) where the cooperative combination of multiple approaches (chemotherapy, magnetic therapy, and PDT) enhanced CDT efficiency against colon cancer.

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