Nanoparticle-Mediated CRISPR Delivery Systems for Targeted Gene Therapy in Metastatic Melanoma: A Comparative Analysis of Blood-Brain Barrier Penetration Efficacy

Abstract

Metastatic melanoma represents one of the most aggressive forms of skin cancer, with brain metastases occurring in approximately 40-60% of advanced cases and presenting formidable therapeutic challenges due to the blood-brain barrier (BBB). The emergence of CRISPR-Cas9 gene-editing technology has opened unprecedented avenues for targeted cancer therapy, yet its clinical translation remains hindered by delivery inefficiencies, particularly in crossing the BBB. This comprehensive review examines the current landscape of nanoparticle-mediated CRISPR delivery systems specifically designed for metastatic melanoma with central nervous system involvement. Through comparative analysis of lipid-based nanoparticles, polymeric carriers, inorganic nanoparticles, and hybrid systems, this study evaluates their respective BBB penetration efficacies, targeting capabilities, and therapeutic outcomes. Recent advances demonstrate that surface-modified nanoparticles conjugated with transferrin, lactoferrin, or cell-penetrating peptides can achieve BBB permeability rates ranging from 2.3% to 8.7%, representing significant improvements over conventional delivery methods. Furthermore, this analysis explores the mechanistic pathways of nanoparticle-mediated transcytosis, receptor-mediated endocytosis, and adsorptive-mediated transport across brain endothelial cells. The integration of stimuli-responsive release mechanisms and active targeting moieties has demonstrated enhanced accumulation in melanoma brain metastases while minimizing off-target effects. This research provides critical insights for developing next-generation therapeutic strategies that could transform the treatment paradigm for one of oncology's most challenging malignancies.