Chondroitin sulfate-based dissolvable microneedles loaded with NIR-II photothermal and natural anticancer agents for synergistic melanoma therapy.

Melanoma is characterized by its aggressiveness, high metastatic potential, and numerous mutations, which limit the effectiveness of current treatments. To address this issue, we developed a dissolvable microneedle (MN) system composed of poly(2-ethyl-2-oxazoline) (PEtOz) and chondroitin sulfate (CS). This MN system was loaded with liposomes containing both a NIR-II photothermal small molecule (IRLy) and the natural anticancer agent Gambogic acid (GA), forming Lip(IRLy + GA) MNs. The integration of the dissolvable microneedle with drug-loaded liposomes aligns with the mechanical properties and skin penetration efficiency required for effective drug delivery. It enables minimally invasive, painless, and precise administration of IRLy and GA. Under NIR-II 1064 nm laser irradiation, Lip(IRLy + GA) effectively inhibited melanoma by disrupting blood vessels, inducing apoptosis, and altering mitochondrial membrane potential. In a subcutaneous melanoma (A375) model in nude mice, the combination of Lip(IRLy + GA) and laser treatment demonstrated a synergistic effect, enhancing both photothermal and chemotherapeutic outcomes. This research presents a promising strategy that combines NIR-II photothermal agents with natural chemotherapeutic drugs and highlights the potential of microneedles in combination therapies for superficial skin cancers like melanoma.