Dissolving Microneedles Loaded with Lipid Nanoparticles for Co-Delivery of siTNF-α and Dexamethasone as a Dual-Action Therapy for Psoriasis.

Psoriasis, a chronic inflammatory skin disease, presents treatment challenges including systemic side effects and inadequate topical drug delivery. Herein, we developed a hyaluronic acid (HA)-based dissolving microneedle platform delivering tumor necrosis factor-alpha (TNF-α)-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-α 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-α 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.