Bioactive M2 exosome hybrid nanocomposites for immune therapy of psoriasis

Psoriasis is a chronic autoimmune skin disease characterized by persistent oxidative stress and sustained inflammation, affecting approximately 1-8% of the global population, with no curative therapy has been well-established to date. To address this, we developed a bioactive hybrid nanocomposite (Exo-Ce) by chemically conjugating M2 macrophage-derived exosomes with cerium oxide nanoparticles (CeNP), which was applied for synergistic and immunomodulatory therapy of psoriasis. This nanohybrid system effectively integrates the natural immunomodulatory properties of exosomes with the reliable antioxidant enzyme-mimetic activities of CeNP. In vitro, mild thiol-maleimide click chemistry minimizes exosome damage; Exo-Ce maintains parental M2-exosome core bioactivity and exhibits ROS-scavenging capacity, significantly reducing intracellular ROS levels and suppressing the secretion of pro-inflammatory cytokines (IL-6 and TNF-α). Following subcutaneous administration in an imiquimod (IMQ)-induced psoriasis mouse model, Exo-Ce markedly ameliorated psoriatic lesions, as evidenced by reduced lesional area, attenuated epidermal hyperkeratosis and acanthosis, and decreased immune cell infiltration. More specifically, Exo-Ce could promote the polarization of macrophages toward an anti-inflammatory M2 phenotype via its ROS-scavenging activity, as well as downregulate key psoriasis-associated cytokines (e.g., IL-1β and TNF-α), thereby facilitating the restoration of tissue homeostasis in vivo. Altogether, our findings position Exo-Ce as a biocompatible and synergistic nanohybrid platform for psoriasis immunotherapy, potentially offering a promising strategy for clinical translation.