Mitochondria–Nanozyme Hybrid Therapeutic for Modulation of the Inflammatory Cascade in Psoriasis

Abstract

The chronic recurrence of psoriasis is driven by a self-amplifying inflammatory cascade in which oxidative stress and mitochondrial metabolic dysfunction reinforce each other, and single-target conventional therapies often fail to break this cycle. Here, we present a micro–nano hybrid system, Mito-Ce, constructed by covalently immobilizing ceria nanozymes (CeNPs) onto the surface of isolated functional mitochondria through thiol–maleimide chemistry. This design endows the hybrid with dual functionalities, including mitochondrial bioactivity and durable ROS-scavenging capabilities of CeNPs. In H₂O₂-stimulated macrophages, upon internalization. Mito-Ce markedly reduced intracellular ROS and consequently suppressed the secretion of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Topical application of Mito-Ce to an imiquimod-induced mouse model of psoriasis visibly resolved psoriatic plaques, reduced the PASI score, and reversed epidermal hyperplasia. Beyond local repair, Mito-Ce rebalanced systemic immunity, evidenced by a decline in splenic pathogenic Th17 cells and polarization toward anti-inflammatory M2 macrophages. Transcriptomic profiling further revealed that Mito-Ce broadly reversed the pathological gene expression program, downregulating stress-responsive and phagocytosis-related genes while upregulating genes associated with metabolism, epidermal proliferation, and tissue homeostatic remodeling. These coordinated networks ultimately re-established immune–barrier homeostasis at the molecular level. Collectively, by integrating nanozyme-mediated ROS scavenging with mitochondrial bioactivity, the Mito-Ce hybrid could treat psoriasis through coordinated disruption of the inflammatory cascade, potentially offering a highly effective platform for various chronic inflammatory disorders.