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

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.