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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 \u03b1-ketoglutarate (\u03b1-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\n                      <jats:italic>Bletilla striata<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12951-026-04533-9","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T04:52:59Z","timestamp":1779079979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microneedle-mediated transdermal delivery of siRNA-loaded nanoparticles for atopic dermatitis therapy by disrupting cuproptosis-pyroptosis crosstalk"],"prefix":"10.1186","volume":"24","author":[{"given":"Pian","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhisheng","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxuan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaozhi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"issue":"2","key":"4533_CR1","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1111\/bjd.19580","volume":"184","author":"MR Laughter","year":"2020","unstructured":"Laughter MR, Maymone MBC, Mashayekhi S, Arents BWM, Karimkhani C, Langan SM, et al. 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