Microneedle-mediated transdermal delivery of siRNA-loaded nanoparticles for atopic dermatitis therapy by disrupting cuproptosis-pyroptosis crosstalk

Abstract Background Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by epidermal barrier dysfunction and immune dysregulation, yet effective long-term therapies are limited. Although regulated cell death has been linked to AD, the involvement of copper-dependent cell death (cuproptosis) and its therapeutic relevance in AD have not been explored. Results Herein, we identify aberrant epidermal upregulation of the copper transporter SLC31A1 as a driver of copper overload and cuproptosis in keratinocytes, which in turn promotes GSDMA-dependent pyroptosis through an α-ketoglutarate (α-KG)/H3K9me3 epigenetic mechanism. To target this pathway, we developed a dual-functional microneedle system composed of calcium phosphate nanoparticles delivering Slc31a1 siRNA and embedded within Bletilla striata polysaccharide microneedles (CaP-siSlc31a1@BSP). This platform enables efficient transdermal gene silencing while BSP simultaneously suppresses STAT3/GSDMA signaling and inflammation. In MC903-induced AD-like mice, CaP-siSlc31a1@BSP markedly alleviated skin inflammation, epidermal hyperplasia and pruritus, accompanied by reduced Th2/Th17 responses. Conclusions Our study reveals a previously unrecognized cuproptosis-pyroptosis axis in AD and establishes SLC31A1 as a promising therapeutic target. The CaP-siSlc31a1@BSP microneedle offers a synergistic drug-gene transdermal strategy with strong potential for AD treatment. Graphical Abstract