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Herein, we developed a hyaluronic acid (HA)-based dissolving microneedle platform delivering tumor necrosis factor-alpha (TNF-\u03b1)-targeting small interfering RNA (siRNA) and dexamethasone co-loaded within dual-functional lipid nanoparticles (LNPs). This LNP design innovatively integrates dexamethasone into its lipid structure, combined with siRNA to enhance stability and anti-inflammatory efficacy while minimizing immunogenicity. The HA microneedles enabled localized, minimally invasive delivery of LNPs into psoriatic lesions. Physicochemical characterization confirmed stable co-loading of siRNA and dexamethasone, with dexamethasone enhancing both LNP stability and siRNA protection. In-vitro studies demonstrated a dual-action mechanism: Dexamethasone suppressed inflammatory signaling pathways while siRNA silenced TNF-\u03b1 expression, leading to superior inhibition of key proinflammatory cytokines. In a psoriasis-like mouse model, this combinatorial strategy significantly reduced disease severity, normalized epidermal hyperplasia, and decreased immune cell infiltration compared to single-agent therapies. The structural incorporation of dexamethasone within LNPs represents a critical advancement, enabling localized immunomodulation that mitigates systemic risks while amplifying TNF-\u03b1 suppression. This integrated approach achieved sustained therapeutic effects with reduced dosing frequency. By co-delivering gene silencing and pharmacological agents via a patient-compliant dissolving microneedle system, our work establishes a precision medicine strategy for psoriasis management, addressing both inflammatory pathways and drug delivery limitations.<\/jats:p>","DOI":"10.1021\/acsami.6c12530","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T22:01:35Z","timestamp":1789423295000},"page":"51417-51430","source":"Crossref","is-referenced-by-count":0,"title":["Dissolving Microneedles Loaded with Lipid Nanoparticles for Co-Delivery of siTNF-\u03b1 and Dexamethasone as a Dual-Action Therapy for Psoriasis"],"prefix":"10.1021","volume":"18","author":[{"given":"Yaxin","family":"Cheng","sequence":"first","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Han","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Gu","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulu","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidan","family":"Tang","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gao","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8278-3912","authenticated-orcid":true,"given":"Chenjie","family":"Xu","sequence":"additional","affiliation":[{"name":"City University of Hong Kong , , ,","place":["Hong Kong SAR, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0561-547X","authenticated-orcid":true,"given":"Guodong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Wuyi University , , ,","place":["Jiangmen, China, 529020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-2143","authenticated-orcid":true,"given":"Ying","family":"Zheng","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, China, 999078"]},{"name":"University of Macau , , ,","place":["Macau, China, 999078"]},{"name":"University of Macau , , ,","place":["Macau, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"issue":"4","key":"2026102013065971500_cit1","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1080\/09546634.2021.1961998","article-title":"Efficacy, safety, and drug survival of IL-23, IL-17, and TNF-alpha inhibitors for psoriasis treatment: a retrospective study","volume":"33","author":"Dapavo","year":"2022","journal-title":"J. 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