Targeting Melanoma-Specific Tyrosinase Disrupts Cytoskeleton Dynamics for Precision Apoptosis Induction by a De Novo
Ruoyang Zhao1,2,3, Xiaowei Wang4, Jiajia Hu1,3
1Joint Medical Engineering Interdisciplinary Research Center of Wenzhou Institute University of Chinese Academy of Sciences and the Affiliated Second Hospital Xiangshan Hospital Wenzhou Medical University Wenzhou Zhejiang China.
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.
Insights
A novel cyclic peptide targets melanoma by disrupting the actin cytoskeleton via tyrosinase-guided nanostructure assembly. This enzyme-instructed therapy shows potent antitumor effects with minimal toxicity, offering a new approach for melanoma treatment.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Melanoma is an aggressive cancer resistant to conventional therapies.
- Existing treatments face challenges with toxicity and acquired resistance.
- There is a critical need for targeted therapies with improved safety and efficacy.
Purpose of the Study:
- To develop a novel tyrosinase-guided cyclic peptide for targeted melanoma therapy.
- To investigate the mechanism of enzyme-instructed supramolecular assembly for cancer treatment.
- To evaluate the therapeutic potential of the peptide in preclinical models.
Main Methods:
- Design and synthesis of a tyrosinase-guided cyclic peptide (c-RGDKYQ).
- Investigation of intracellular oxidation and supramolecular nanostructure assembly.
- Assessment of effects on melanoma cell migration, adhesion, proliferation, and apoptosis.
- Evaluation of antitumor activity and tolerability in a murine B16 melanoma model.
- Transcriptomic profiling to confirm cytoskeletal disruption.
Main Results:
- The cyclic peptide c-RGDKYQ self-assembles into nanostructures within tyrosinase-expressing melanoma cells.
- These nanosystems selectively destabilize the actin cytoskeleton, inhibiting melanoma cell functions.
- The peptide demonstrated potent antitumor activity in a murine model with minimal off-target effects.
- Cytoskeletal collapse was confirmed by gene expression analysis.
Conclusions:
- A minimalist, enzyme-responsive peptide platform can achieve targeted melanoma therapy via physical cytoskeletal disruption.
- Tyrosinase-guided supramolecular assembly offers a novel strategy for cancer treatment.
- This approach holds promise for treating other malignancies with dysregulated metabolic enzymes.
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