Artesunate nanoliposome-hydrogel: a dual-modal therapy for post-surgical melanoma.

Background: Melanoma management faces the dual challenge of preventing tumor recurrence while ensuring optimal post-surgical wound healing, particularly problematic given melanoma's high recurrence rates and therapeutic resistance. Artesunate (ARS) emerges as a promising multimodal agent with concurrent anticancer, anti-inflammatory, and tissue-regenerative properties. However, its anti-melanoma mechanisms remain incompletely characterized, and clinical translation has been limited by suboptimal pharmacokinetics. Methods: We employed transcriptomic profiling (RNA-seq) to identify novel ARS-regulated pathways. Subsequently, we developed an optimized drug delivery system comprising: amphiphilic nanoliposomes for efficient ARS encapsulation and enhanced cellular internalization, and a carboxymethyl chitosan hydrogel matrix (ARS-LS-Gel) engineered to provide sustained drug release while promoting tissue regeneration. Comprehensive physicochemical characterization preceded systematic in vitro evaluation in melanoma (B16F10, A375) and normal cell models, assessing cytotoxicity, cellular uptake, and mechanistic pathways. Dual efficacy was quantified in vivo using syngeneic melanoma and full-thickness wound healing models. Results: The ARS-LS-Gel system demonstrated optimal physicochemical characteristics, including well-dispersed particles, sustained drug release kinetics and exceptional biocompatibility. It potently induced melanoma cell apoptosis through p53-mediated mitochondrial dysfunction, characterized by: (1) sustained ROS accumulation, (2) cytochrome C release, (3) mitochondrial membrane potential collapse, (4) impaired ATP synthesis, and (5) calcium overload. In vivo, the platform significantly suppressed tumor progression, evidenced by enhanced apoptosis and reduced Ki-67 expression. Concurrently, it accelerated wound regeneration via targeted downregulation of pro-inflammatory mediators (TNF-α, IL-1β) and enhanced collagen deposition. Conclusion: The ARS-LS-Gel platform's ability to simultaneously address oncogenic progression and tissue repair represents a significant conceptual and practical advancement in post-surgical cancer management. By bridging fundamental mechanistic discovery with engineered therapeutic delivery, our findings provide a robust foundation for imminent translational development in melanoma therapy and beyond.