Drug-loaded microneedle patches containing regulatory T cell-derived exosomes for psoriasis treatment.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia, skin inflammation, and immune dysregulation. These factors contribute to the persistent progression of the disease. While addressing excessive keratinocyte proliferation or inhibiting inflammation may provide temporary therapeutic relief, unresolved immune dysregulation often exacerbates the condition. Therefore, comprehensive treatments that alleviate skin symptoms and regulate immune tolerance are urgently required. An ideal treatment would target multiple factors, including keratinocyte proliferation, inflammation, and immune tolerance, while minimizing systemic side effects. In this study, we developed a dissolvable hyaluronic acid microneedle patch containing regulatory T cell (Treg) exosomes loaded with dimethyl fumarate (DMF) (rExo@DMF MNs). DMF acts as an inhibitor of keratinocyte proliferation and an anti-inflammatory agent through NF-κB suppression and Nrf2 activation, inhibiting the production of pro-inflammatory cytokines and the activation of inflammatory cells. Delivering DMF via Treg exosomes enhances its retention at the lesion site. This system inhibits keratinocyte proliferation and migration, reduces pro-inflammatory cytokine release, and alleviates epidermal hyperplasia and inflammation in an imiquimod-induced psoriasis mouse model. Additionally, Treg exosomes modulate immune responses to promote tolerance. rExo@DMF MNs demonstrate immunomodulatory effects by inhibiting T helper 17 (Th17) cells and inducing regulatory immune cells such as Tregs and tolerogenic dendritic cells (tDCs) differentiation. rExo@DMF MNs alleviate skin symptoms and regulate immune cells in the skin, spleen, and lymph nodes, demonstrating both local and systemic immunoregulation with promising therapeutic potential for psoriasis. STATEMENT OF SIGNIFICANCE: Novel therapies are urgently needed to alleviate skin symptoms and regulate immunity, as current psoriasis treatments focus on symptom relief while neglecting the underlying immune dysfunction, resulting in limited efficacy. Moreover, systemic immunosuppression often leads to severe side effects. This study introduces a hybrid microneedle system (rExo@DMF MNs) that alleviates psoriasis symptoms and modulates immune responses locally and systemically. In addition, rExo@DMF MNs penetrate hyperkeratotic skin, ensuring targeted rExo@DMF release while minimizing systemic exposure and side effects. All components of the system, including hyaluronic acid (a key component of the skin matrix), regulatory T cell-derived exosomes, and DMF (a clinically validated drug), exhibit biocompatibility. This comprehensive approach addresses multiple pathogenic factors, promising an effective and safe psoriasis treatment.