Dual-Responsive and ROS-Augmented Nanoplatform for Chemo/Photodynamic/Chemodynamic Combination Therapy of Triple Negative Breast Cancer

Integrating chemodynamic therapy (CDT) and photodynamic therapy (PDT) into one nanoplatform can produce much more reactive oxygen species (ROS) for tumor therapy. Nevertheless, it is still a great challenge to selectively generate sufficient ROS in tumor regions. Meanwhile, CDT and PDT are restricted by insufficient H₂O₂ content in the tumor as well as by the limited tumor tissue penetration of the light source. In this study, a smart pH/ROS-responsive nanoplatform, Fe²⁺@UCM-BBD, is rationally designed for tumor combination therapy. The acidic microenvironment can induce the pH-responsive release of doxorubicin (DOX), which can induce tumor apoptosis through DNA damage. Beyond that, DOX can promote the production of H₂O₂, providing sufficient materials for CDT. Of note, upconversion nanoparticles at the core can convert the 980 nm light to red and green light, which are used to activate Ce6 to produce singlet oxygen (¹O₂) and achieve upconversion luminescence imaging, respectively. Then, the ROS-responsive linker bis-(alkylthio)alkene is cleaved by ¹O₂, resulting in the release of Fenton reagent (Fe²⁺) to realize CDT. Taken together, Fe²⁺@UCM-BBD exhibits on-demand therapeutic reagent release capability, excellent biocompatibility, and remarkable tumor inhibition ability via synergistic chemo/photodynamic/chemodynamic combination therapy.