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.