Transdermal siRNA delivery via biomineralized nanoparticle-incorporated microneedles modulates cuproptosis-ferroptosis interaction for psoriasis therapy

Psoriasis is a chronic immune-mediated skin disorder driven by abnormal keratinocyte proliferation and inflammation, and the dysregulation of copper transport is increasingly recognized as a key metabolic driver and potential therapeutic target in psoriasis. Herein, we identified solute carrier family 31 member 1 (SLC31A1) as a pivotal molecular switch connecting cuproptosis and ferroptosis, two interconnected forms of regulated cell death that synergistically promote psoriatic pathology. Upregulated SLC31A1 induces copper accumulation and elevates α-ketoglutarate (α-KG), activating KDM5B-dependent histone demethylation and repressing FTH1 transcription, thereby amplifying ferroptotic damage and inflammation. To therapeutically target this axis, we developed a nanoparticle-incorporated microneedle system (CaP-siSlc31a1@MN) enabling localized, efficient and minimally invasive siRNA delivery through the psoriatic barrier. The dissolvable microneedles with favorable mechanical performance ensured precise epidermal deposition, while biomineralized calcium phosphate (CaP) nanoparticles facilitated intracellular uptake and siRNA release. In vitro and in vivo studies confirmed that CaP-siSlc31a1@MN effectively silenced Slc31a1, inhibited cuproptosis and ferroptosis, suppressed IL17A-driven inflammation and restored epidermal homeostasis. Overall, this study introduces a first-in-class transdermal gene-silencing nanoplatform that integrates metabolic regulation with anti-inflammatory therapy for precision psoriasis treatment. • SLC31A1 was identified as a key regulator linking cuproptosis and ferroptosis in psoriasis. • Silencing SLC31A1 restored FTH1 expression and suppressed copper overload-driven metabolic inflammation. • Biomineralized CaP-siSlc31a1 nanoparticles were integrated into dissolvable microneedles for efficient transdermal Slc31a1 siRNA delivery. • The dissolvable microneedle achieves precise epidermal deposition, reduced Th17 infiltration and marked attenuation of IMQ-induced psoriasis-like dermatitis. • This work introduces a translatable microneedle-based gene-silencing strategy for precision psoriasis therapy.