Intelligent Nanoplatform with Multi Therapeutic Modalities for Synergistic Cancer Therapy

Chemodynamic therapy (CDT) has attracted increasing attention in tumor treatment but is limited by insufficient endogenous H₂O₂. Moreover, it is challenging for monotherapy to achieve a satisfactory outcome due to tumor complexity. Herein, we developed an intelligent nanoplatform that could respond to a tumor microenvironment to induce efficient CDT without complete dependence on H₂O₂ and concomitantly generate chemotherapy and oncosis therapy (OT). The nanoplatform was constructed by a calcium- and iron-doped mesoporous silica nanoparticle (CFMSN) loaded with dihydroartemisinin (DHA). After entering into cancer cells, the nanoplatform could directly convert the intracellular H₂O₂ into toxic •OH due to the Fenton-like activity of CFMSN. Meanwhile, the acidic microenvironment and endogenous chelating molecules triggered Ca²⁺ and Fe³⁺ release from the nanoplatform, causing particle collapse with accompanying DHA release for chemotherapy. Simultaneously, the released Ca²⁺ induced intracellular Ca²⁺-overloading for OT, which was further enhanced by DHA, while the released Fe³⁺ was reduced to reactive Fe²⁺ by intracellular glutathione, guaranteeing efficient Fenton reaction-mediated CDT. Moreover, Fe²⁺ cleaved the peroxy bonds of DHA to generate C-centered radicals to further amplify CDT. Both in vitro and in vivo results confirmed that the nanoplatform exhibited excellent anticancer efficacy via the synergistic effect of multi therapeutic modalities, which is extremely promising for high-efficient cancer therapy.