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 Foxp3 expression, and thereby inhibits both the differentiation of naı̈ve CD4 + T cells into Tregs under Treg-polarizing conditions and their TGF-β1 secretion in vitro . 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 p < 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.