A Self-Assembled Copper-Selenocysteine Nanoparticle for Enhanced Chemodynamic Therapy via Oxidative Stress Amplification

Chemodynamic therapy (CDT) as a catalytic anticancer strategy utilizes transition metal ions to initiate the Fenton reaction to produce high levels of cytotoxic hydroxyl radicals(·OH) in situ. Nevertheless, current existing CDTs are normally restricted by the high levels of existing antioxidant molecules and/or enzymes, such as glutathione (GSH) and thioredoxin reductase (TrxR), in a tumor internal environment, which could suppress CDT via ·OH depletion. Herein, to enhance ·OH-induced cellular damage by CDT, a self-assembled copper-selenocysteine nanoparticles (Cu-SeC NPs) was fabricated through a one-pot process. In our design, once Cu-SeC NPs were endocytosed by tumor cells, Cu 2+ was reduced to Cu + by cellular GSH, promoting in situ Fenton-like reactions to trigger ·OH rapid production in cells as well as the depletion of GSH. Furthermore, the gradually released selenocysteine can inhibit TrxR activity to weaken the protection of antioxidant systems and provide a favorable microenvironment for CDT. As a result, both paths synergistically resulted in massive reactive oxygen species (ROS) accumulation and amplified oxidative stress in tumor sites for enhanced CDT. As a new intelligent anticancer nanoplatform, Cu-SeC NPs exhibit synergistic antitumor effects with negligible systemic toxicity. Thus, the proposed strategy provides a new avenue for further development of progressive therapeutic systems.