AND Logic Gate Strategy for Targeted Melanoma Treatment Through Sequential Photosynthetic Oxygenation and Tyrosinase-Catalyzed Ferroptosis.

Malignant melanoma is a highly aggressive and metastatic skin cancer characterized by tyrosinase overexpression. Therefore, harnessing the activation of tyrosinase-catalyzed toxicity enables targeted tumor-specific therapy while sparing surrounding healthy tissues. Herein, an AND logic-gated, cyanobacteria (Cyan)-driven, living therapeutic alginate hydrogel is proposed that activates the tyrosinase-catalyzed ferroptotic phenolic prodrug N-(4-hydroxyphenyl) acetamide (APhH), triggering cascaded reactive oxygen species (ROS) generation and glutathione (GSH) depletion for melanoma-specific ferroptosis. The therapeutic mechanism operates through a sequential dual-input procedure: microorganism-driven photosynthetic oxygenation and endogenous tyrosinase catalysis. Light-activated Cyan performs photosynthetic oxygen production, alleviating tumor hypoxia while acting as the essential cofactor for tyrosinase. Once activated, tyrosinase catalyzes the conversion of APhH into the cytotoxic benzoquinone derivative, 4-acetamido-o-benzoquinone (APhQ). Concurrently, oxygen is transformed into ROS, synergizing with APhQ to deplete GSH for glutathione peroxidase 4 inactivation, thereby promoting lipid peroxide generation. The combined effects of ROS generation, GSH depletion, and lipid peroxide accumulation culminate in a potent ferroptotic response, selectively targeting melanoma cells while sparing healthy tissue. This study highlights the potential of an AND logic-gated approach for achieving highly specific, targeted prodrug activation, enhancing precision in melanoma treatment.