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Proprotein convertase subtilisin\/kexin type 9 (PCSK9), a pivotal regulator of lipid metabolism, has recently been implicated in keratinocyte hyperproliferation and immune dysregulation in psoriasis.However, transdermal delivery of siRNAs forPCSK9 inhibition is challenging.To address this limitation, we developed a dissolvable microneedle (MN) platform encapsulating mesenchymal stem cell (MSC)\u2010derived biomimetic nanovesicles (MSCNV) loaded with siPCSK9 (MN\u2010MSCNV@siPCSK9). This integrated platform facilitates stabilized siRNA encapsulation via MSCNV\u2010mediated protection, enables efficient transdermal delivery via stratum corneum disruption, and leverages MSCNV's inherent bioactivity for synergistic immunomodulation. In vitro, MN\u2010MSCNV@siPCSK9 significantly inhibited keratinocyte proliferation and pro\u2010inflammatory cytokine secretion. In vivo, it alleviated imiquimod (IMQ)\u2010induced psoriasis symptoms by reducing epidermal hyperplasia and systemic inflammation. Mechanistically, the platform suppressed nuclear factor\u2010kappa B (NF\u2010\u03baB) pathway activation, modulated Th1, Th2, and Th17 cell subsets, and disrupted the inflammatory crosstalk between keratinocytes and immune cells. Consequently, it coordinately regulates both local and systemic inflammatory microenvironments. This study establishes a translatable \u201cencapsulation\u2010delivery\u2010modulation\u201d strategy, providing a potent gene\u2010silencing platform for precision psoriasis therapy.<\/jats:p>","DOI":"10.1002\/adhm.202504232","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:03:34Z","timestamp":1766124214000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transdermal Delivery of PCSK9 siRNA via Biomimetic Nanovesicle\u2010Loaded Microneedles for Psoriasis Immunomodulation"],"prefix":"10.1002","volume":"15","author":[{"given":"Hanxue","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei China"},{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaye","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei China"},{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei China"},{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiying","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0574-4020","authenticated-orcid":false,"given":"Quangang","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5603-745X","authenticated-orcid":false,"given":"Zongguang","family":"Tai","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3789-7096","authenticated-orcid":false,"given":"Zhongjian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei China"},{"name":"School of Medicine Shanghai Skin Disease Hospital Tongji University  Shanghai China"},{"name":"Shanghai Engineering Research Center of External Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"issue":"10281","key":"e_1_2_11_2_1","first-page":"1301","volume":"397","author":"Griffiths C. 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