Engineered Mesenchymal Stem Cell‐Derived Extracellular Vesicles Scavenge Self‐Antigens for Psoriasis Therapy via Modulating Metabolic and Immunological Disorders

Abstract Psoriasis is a chronic inflammatory dermatosis driven by excessive activation of the immune system. Recent studies have demonstrated the therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) to psoriasis because of their immunomodulation functions. Yet, the outcome of MSC‐EVs alone is still unsatisfactory and the underlying mechanisms are also unclear. Here, it is uncovered that arginase1 (Arg1)/polyamine is overexpressed in psoriasis patients and murine, inducing the in‐situ accumulation of self‐antigens. Engineered nor@MSC‐EVs are fabricated by loading Arg1 inhibitor nor‐NOHA into MSC‐EVs for studying the therapeutic effect and mechanism of psoriasis. The nor@MSC‐EVs exhibited profound suppression of the NF‐κB signaling pathway by targeting Arg1/polyamine‐mediated DCs/Th17 axis through scavenging self‐antigens, resulting in superior mitigation of skin lesions and modulation of local and systemic metabolic and immunological disorders compared to the MSC‐EVs and clinically used anti‐IL17A both in vitro and in vivo. Together, the results highlight a novel perspective for psoriasis therapy by nor@MSC‐EVs with broad clinical translational potential.