Pt@FeMOF-PEG Nanozyme-Mediated Reactive Oxygen Species Scavenging and Reduction of Treg Cells To Treat Surgical Trauma

Postoperative immunosuppression, which is closely associated with the oxidative-stress-driven expansion of regulatory T cells (Tregs), increases susceptibility to severe postoperative outcomes, including infectious complications, multiple organ dysfunction syndrome (MODS), and tumor progression. Here, we report a zirconium-based metal-organic framework (MOF) cascade nanozyme, designated "Pt@PCN-224-Fe", coated with poly(ethylene glycol) (Pt@FeMOF-PEG) that simultaneously mimics superoxide dismutase (SOD) and catalase (CAT) to neutralize excessive reactive oxygen species (ROS). Mechanistically, scavenging ROS reactivates the PI3K-AKT-mTOR signaling axis, suppresses <i>Foxp3</i> expression, and thereby inhibits both the differentiation of naı̈ve CD4⁺ T cells into Tregs under Treg-polarizing conditions and their TGF-β1 secretion <i>in vitro</i>. In a murine model of surgical trauma, the single intraperitoneal administration of Pt@FeMOF-PEG reversed immunosuppression within 72 h, evident as a reduced frequency of Tregs, expanded Th17 cells, normalized CD4⁺/CD8⁺ ratio, and suppressed M2 macrophage polarization (all <i>p</i> < 0.05). Concurrently, proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ) increased, whereas anti-inflammatory cytokines (IL-4, IL-10) decreased, indicating the systemic reinvigoration of the innate and adaptive immunity. The nanozyme showed excellent biocompatibility, with negligible hemolysis (<5%), no histological organ damage, and minimal systemic toxicity. In this work, we have developed a dual-enzyme-mimicking nanozyme (Pt@FeMOF-PEG) that precisely targets the ROS-PI3K-Treg axis in a single-dose strategy to reverse postoperative immune dysfunction, thus addressing a long-unmet clinical requirement for surgical recovery.