Engineering inhaled mucus-penetrating MOFs-based nanozymes to combat ferroptosis-driven inflammatory cascades in acute lung injury

The clinical management of acute lung injury (ALI) remains constrained by pulmonary mucus barriers that impede therapeutic penetration and complex pathophysiology involving oxidative stress amplification and dysregulated inflammation. We report an engineered nanotherapeutic platform featuring poloxamer 124-functionalized cerium-tannic acid coordination metal-organic frameworks-based nanozymes (Ce-TA@124) that surmount the aforementioned biological barriers through a multi-tiered therapeutic strategy. Demonstrating superior efficacy to dexamethasone benchmarks, this system achieves: (1) synergistic reactive oxygen species scavenging enabled by Ce 3+ /Ce 4+ interconversion and excellent reducing capacity from polyphenolic TA; (2) macrophage repolarization toward M2 pro-healing phenotypes via cytokine storm mitigation (IL-1β, IL-6, TNF-α); and (3) dual cell death pathway inhibition through apoptosis suppression and GPX4-mediated ferroptosis blockade. The mucus-penetrating poloxamer 124 corona enables rapid diffusion (4-fold higher) and alveolar deposition (2.67-fold enhancement) while preserving biocompatibility. Mechanistic profiling reveals TLR4-MAPK-NF-κB signaling axis modulation as the cornerstone of anti-inflammatory action, coupled with Nrf2 pathway activation for redox homeostasis restoration. Through comprehensive in vivo validation demonstrating a 65% reduction in lung injury scores and complete survival protection in ALI-acute respiratory distress syndrome models, this work establishes Ce-TA@124 as a paradigm-shifting nanoplatform that addresses both pathological drivers and delivery challenges in pulmonary inflammation management, with significant clinical translation potential.