Abstract

Hypertrophic scar (HS) is a pathologic fibrotic disease caused by aberrant wound healing following severe skin injury. Despite advances in clinical treatments, the therapeutic outcomes remain suboptimal, mainly due to inadequate penetration through the thickened stratum corneum barrier and insufficient site-specific drug delivery within the lesional tissue. To address these limitations, we developed a hyaluronic acid-based dissolving microneedle array loaded with reactive oxygen species (ROS)-responsive asiatic acid nanoparticles (AA/PTP MN). This advanced platform facilitates direct intradermal delivery of therapeutic agents by penetrating the stratum corneum. Upon dissolution in the scar tissue, the released AA/PTP nanoparticles respond to the elevated ROS levels, enabling precise and sustained release of asiatic acid (AA) to actively remodel the pathological microenvironment. This innovative nano-micro platform exhibited excellent ROS sensitivity, robust mechanical properties, and good biocompatibility. In vitro experiments revealed that AA/PTP can specifically inhibited the proliferation of hypertrophic scar fibroblasts and reduced macrophage migration. In the rabbit ear HS model, AA/PTP MN treatment effectively remodeled the pathological HS microenvironment, as evidenced by significantly reduced scar thickness, normalized collagen architecture, and marked inhibition of skin fibrosis. RNA sequencing analysis confirmed that this therapeutic effect was achieved through multi-faceted regulation of the scar microenvironment: inhibiting fibroblast and keratinocyte proliferation, attenuating inflammation, and reducing excessive collagen deposition. In summary, this microneedle-based strategy of microenvironment-specific drug release represents a promising and effective therapeutic avenue for achieving scarless regeneration in hypertrophic scars.