Soft-hard immune taming: a macrophage-targeted GPx-like nanozyme reprograms immunometabolism for acute lung injury therapy

Acute lung injury (ALI) is a life‑threatening disorder driven by a self‑amplifying cycle between excessive reactive oxygen species (ROS) accumulation and macrophage‑mediated hyperinflammation, which can develop into acute respiratory distress syndrome (ARDS) with limited targeted therapies. A novel host‑centric strategy termed soft-hard synergistic immune taming is proposed to disrupt the self‑amplifying inflammatory circuit in ALI. An intelligent nanodelivery system named LF@MVN‑4OI is designed, which combines a V(III)‑based metal‑organic framework nanozyme (MVN) with glutathione peroxidase (GPx)‑like activity and phospholipid‑modified 4‑octyl itaconate (4OI). Lactoferrin (LF) modification enables targeted delivery to activated macrophages in inflamed lungs and responsive release in high‑ROS and mildly acidic microenvironments. 4OI provides “soft” immunometabolic reprogramming through the itaconate/immune response gene 1 (IRG1) axis, polarizing macrophages towards a pro-resolving phenotype, while MVN exerts a “hard” catalytic redox control effect by decomposing peroxides to mitigate oxidative damage. In vivo, LF@MVN‑4OI effectively alleviates lung inflammation, oxidative damage, and tissue injury. Collectively, this work establishes a multimodal nanotherapeutic that reframes LPS-induced inflammatory ALI management from pathogen eradication toward rapid restoration of pulmonary redox-immune homeostasis, and highlights soft-hard immune taming as a generalizable framework for critical inflammatory lung syndromes.