Abstract

Psoriasis is a chronic autoimmune skin disorder primarily driven by dendritic cells (DCs). However, the full therapeutic potential of antipsoriatic agents like calcipotriol (Cal) hinges on the precise and efficient delivery to DCs. Herein, a nanovehicle fabricated using keratinocyte-derived apoptotic vesicles (apoEVs) is proposed to enhance drug accumulation in DCs and synergistically modulate DC function. Specifically, the phosphatidylserine exposed on the apoEV surface serves as an "eat-me" signal, facilitating specific recognition and engulfment by DCs. This process mimics the natural efferocytic clearance of apoptotic keratinocytes by DCs in the skin. Moreover, apoEVs intrinsically inhibit DC maturation by eliciting efferocytosis-mediated immunosuppressive signals. To enable transdermal administration, Cal-loaded apoEVs were integrated into dissolvable microneedles (MNs). As a consequence, the Cal-apoEV MNs demonstrated superior capability in reprogramming DCs from a pro-inflammatory to a tolerogenic phenotype, thereby suppressing the pathogenic inflammatory loop and ameliorating psoriatic symptoms. Notably, Cal-apoEV MNs remodeled the psoriatic immune microenvironment toward a tolerogenic state, characterized by enhanced regulatory T cell infiltration. The present study reveals that the keratinocyte-derived nanovehicles can not only enhance the accumulation of Cal in DCs but also synergistically reprogram DCs, providing a promising strategy for treating immune-mediated skin diseases.