Transdermal Delivery of PCSK9 siRNA via Biomimetic Nanovesicle-Loaded Microneedles for Psoriasis Immunomodulation.

Psoriasis onset is closely associated with abnormal lipid metabolism. 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)-derived biomimetic nanovesicles (MSCNV) loaded with siPCSK9 (MN-MSCNV@siPCSK9). This integrated platform facilitates stabilized siRNA encapsulation via MSCNV-mediated protection, enables efficient transdermal delivery via stratum corneum disruption, and leverages MSCNV's inherent bioactivity for synergistic immunomodulation. In vitro, MN-MSCNV@siPCSK9 significantly inhibited keratinocyte proliferation and pro-inflammatory cytokine secretion. In vivo, it alleviated imiquimod (IMQ)-induced psoriasis symptoms by reducing epidermal hyperplasia and systemic inflammation. Mechanistically, the platform suppressed nuclear factor-kappa B (NF-κB) 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 "encapsulation-delivery-modulation" strategy, providing a potent gene-silencing platform for precision psoriasis therapy.