Construction of a dual-layer microneedle drug delivery system based on “chemotherapy-immunity-anti-inflammatory” for melanoma research

• Localized melanoma treatment offers distinct advantages. • The microneedle delivery system exhibits a dual synergistic effect of cell wall disruption and drug release. • Combining Traditional Chinese Medicine Components with Chemotherapy Drugs to Enhance Efficacy and Reduce Toxicity. • Nucleus-shell nanomedicines enable tiered treatment combining chemotherapy, immunotherapy, and anti-inflammatory effects. Melanoma, the most lethal skin disease with steadily rising incidence rates, demands safer, more precise, and intelligently effective combination therapies. By utilizing traditional Chinese medicine polysaccharides as the microneedle matrix, we developed dual-layer microneedles incorporating multi-core–shell structured nanoparticles and anti-inflammatory immune nanoparticles loaded with both chemical and herbal components. These dual-layer microneedles demonstrate superior synergistic antitumor and anti-inflammatory effects both in vivo and in vitro. Following local administration, they achieve a 95.6% inhibition rate against melanoma, effectively inhibiting tumor growth and invasion. They significantly enhance the activation and immune function of tumor-targeting T cells, increase the proportion of CD8 + T cells, and simultaneously activate innate immune functions in immune organs. This approach boosts the proportion of immune T cells and NK cells in the spleen, promotes T cell secretion of TNF-α to achieve anti-tumor immune activation, and enhances systemic anti-inflammatory immune responses. Simultaneously, it reduces drug concentration in non-targeted areas, minimizing systemic toxicity and side effects. This achieves a tiered drug delivery effect combining “chemotherapy-immunotherapy-anti-inflammation,” realizing a three-pronged synergistic anti-tumor effect through “break the skin barrier −drug release-immune coordination.” It provides a reference for developing new formulations for microneedle local administration and topical anti-tumor preparations.