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

Abstract

<b>Background:</b> 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. <b>Methods:</b> 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 <i>in vitro</i> evaluation in melanoma (B16F10, A375) and normal cell models, assessing cytotoxicity, cellular uptake, and mechanistic pathways. Dual efficacy was quantified <i>in vivo</i> using syngeneic melanoma and full-thickness wound healing models. <b>Results:</b> 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. <i>In vivo</i>, 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. <b>Conclusion:</b> 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.