Synergistic nanozyme-macrophage hybrid system for targeted therapy of acute lung injury

Due to its complex pathogenesis involving dysregulated reactive oxygen species (ROS) storms, cytokine hyperactivation and immune cell infiltration, acute lung injury (ALI) presents critical clinical challenges, and conventional therapies often fail to address the dual requirements of precise inflammatory targeting and microenvironment regulation. Herein, we report an intelligent biomimetic nanosystem (CeGM) featuring (i) synergistic catalytic circuits, where hollow CeO₂ nanoenzymes are combined with glycyrrhizic acid (GA) through density functional theory (DFT)-optimized binding configurations, achieving charge redistribution-induced dual-site catalytic activation relative to conventional CeO₂ alone; (ii) pathology-responsive delivery, where macrophage membrane camouflage enables lipopolysaccharide (LPS) recognition and inflammatory chemotaxis, yielding 7.8-fold higher alveolar accumulation than non-coated counterparts in LPS-induced ALI models; (iii) multidimensional immunomodulation, where NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation (56.20% interleukin-1β (IL-1β) reduction) and M1 macrophage polarization (2.4-fold M2/M1 ratio increase) are concurrently suppressed through GA-mediated nuclear factor kappa B (NF-κB) pathway inhibition and CeO₂-mediated redox homeostasis restoration. This dual-functional nanoplatform demonstrates favourable therapeutic outcomes in mitigating pulmonary edema by clearing ROS (47.20% reduction in ROS levels), neutrophil infiltration (58.16% myeloperoxidase (MPO) activity decrease) and cytokine storms (tumor necrosis factor-alpha (TNF-α) reduction of 45.90%), offering a paradigm-shifting strategy for precision nanomedicine in acute inflammatory disorders.