Nonfouling Core-Shell Microneedle for Sequential and Sustained Drug Release: Enhancing Synergistic Photothermal Chemotherapy in Melanoma Treatment.

Melanoma is a highly aggressive and metastatic malignancy, where current treatment methods often result in damage to healthy tissues, suboptimal therapeutic outcomes, and immune-related side effects. Microneedles, as a drug delivery system, offer advantages such as localized administration, minimal invasiveness, and high delivery efficiency. In this study, we first synthesized tetradecyl-thiol-grafted PAMAM dendrimers, which significantly enhanced cellular uptake and enabled sustained release of doxorubicin (DOX), improving cumulative drug release efficiency. Based on this, we developed a core-shell structured zwitterionic polymer-based microneedle delivery system. The outer shell, loaded with the photothermal agent indocyanine green (ICG), achieved precise photothermal therapy under near-infrared irradiation, effectively targeting melanoma tissues. The inner core, composed of a zwitterionic polymer matrix, encapsulated DOX-loaded dendrimers, enabling controlled and prolonged drug release through gradual polymer swelling and dendrimer expansion. Experiments show that the microneedle drug delivery system based on PAMAM dendrimer grafted with tetradecyl mercaptan and zwitterionic polymer has excellent anti protein adsorption properties, and it can minimize the cytotoxicity of carrier and improve the efficiency of drug delivery. This system effectively inhibited tumor growth through synergistic photothermal-chemotherapy, reducing systemic toxicity and improving drug bioavailability. This microneedle platform provides a promising strategy for targeted and synergistic melanoma therapy, offering a high-efficiency and low-toxicity treatment alternative.