Enhanced Transcutaneous Chemodynamic Therapy for Melanoma Treatment through Cascaded Fenton-like Reactions and Nitric Oxide Delivery.

Chemodynamic therapy (CDT) has emerged as a promising strategy for cancer treatment. However, its effectiveness has been hindered by insufficient hydrogen peroxide (HO) and high reductive glutathione (GSH) within tumors, which are the two main reasons for the inefficiency of Fenton/Fenton-like reaction-based CDT. Herein, we present a HO boost-GSH depletion strategy for enhanced CDT to fight against melanoma through a microneedle (MN)-based transcutaneous delivery method. The MN system is composed of dissolvable polyvinylpyrrolidone integrated with stimuli-responsive prodrugs. Under an intracellular acidic environment, the smart release of HO boosting components is triggered, subsequently initiating nitric oxide (NO) release and enhancing the Fenton-like reaction in a cascade manner. The generation of hydroxyl radicals (OH), along with the depletion of GSH by NO, amplifies the oxidative stress within tumor cells, promoting apoptosis and ferroptosis. The antitumor efficacy of the MN patch is validated in an A375 mouse melanoma model. This "HO boost-GSH depletion-Fenton killing" strategy expands the options for superficial tumor treatment through MN-mediated enhanced CDT.