A procedurally activatable nanoplatform for chemo/chemodynamic synergistic therapy

Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH, hypoxia, and hydrogen peroxide (H₂O₂) overexpression, could enhance the biological activity of the drugs and reduce the side effects. In this study, a H₂O₂/glutathione (GSH) procedurally activatable nanoplatform (Cu₉S₅-PEG/DOX NSs) was prepared as a vector of drugs released by responsive morphologic transformation and the co-activated Fenton agent for tumor-specific synergistic therapy. After endocytosis into tumor cells, Cu₉S₅-PEG/DOX NSs were initially oxidized by over-expressed H₂O₂ and transformed from nanosheets to nanoflowers, leading to the release of doxorubicin (DOX). Subsequently, Cu₉S₅ nanoflowers (Cu₉S₅ NFs) reacted with the local GSH, liberated a large number of copper ions, and induced GSH depletion. The released DOX promoted the generation of intracellular H₂O₂ through cascade reactions, which were further utilized to facilitate the release of DOX and generate toxic hydroxyl radicals (˙OH) via a copper-based Fenton-like reaction. Cu₉S₅-PEG/DOX NSs sequentially activated by H₂O₂ and GSH in tumor cells exhibited relatively high cytotoxicity, whereas normal cells were still alive. This nanoplatform, as a procedurally activatable delivery system, may have excellent potential for tumor-specific synergistic therapy.