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

Abstract 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.