Targeting Melanoma‐Specific Tyrosinase Disrupts Cytoskeleton Dynamics for Precision Apoptosis Induction by a De Novo Designed Cyclic Peptide

ABSTRACT

Melanoma remains highly aggressive and refractory to conventional therapies, with current treatments often limited by toxicity and acquired resistance, underscoring the urgent need for targeted strategies with improved safety and durable efficacy. Here, we report a tyrosinase‐guided cyclic peptide, c‐RGDKYQ, that exploits the overexpression of tyrosinase in melanoma cells to trigger intracellular oxidation and in situ assembly of supramolecular nanostructures. These enzyme‐instructed nanosystems selectively destabilize the actin cytoskeleton, thereby suppressing B16 melanoma cell migration, adhesion, and proliferation, and inducing apoptosis without requiring exogenous drug payloads or complex delivery carriers. This selective activity is strictly dependent on tyrosinase expression, as the linear control peptide lacking conformational constraint showed minimal cytotoxicity. In a murine B16 tumor model, c‐RGDKYQ exhibits potent antitumor activity with minimal off‐target effects and favorable tolerability. Transcriptomic profiling further confirms cytoskeletal collapse, evidenced by coordinated downregulation of actin/tubulin genes and compensatory upregulation of regulatory factors. This work establishes a proof‐of‐concept for a minimalist, enzyme‐responsive peptide platform that achieves targeted melanoma therapy through physical cytoskeletal disruption. Beyond melanoma, this paradigm of enzyme‐directed supramolecular assembly may offer a translatable framework for treating other malignancies characterized by dysregulated metabolic enzymes.