Multifunctional nano-platform for precision treatment of acute lung injury via synergistic anti-inflammation and oxidative stress modulation.

Acute lung injury (ALI) remains life-threatening conditions lacking effective disease-modifying therapies. Dysregulated inflammation, oxidative stress, and apoptosis form a self-amplifying pathogenic loop that drives alveolar-capillary barrier disruption, highlighting the urgent need for multifunctional therapeutic strategies. Here, we report a pH-responsive biomimetic nanoplatform, pDA/Esc@ZIF-8, for precision treatment of ALI. Zeolitic imidazolate framework-8 (ZIF-8) was employed to encapsulate the natural anti-inflammatory and antioxidant agent esculin (Esc), while a polydopamine (pDA) coating conferred enhanced colloidal stability, intrinsic reactive oxygen species scavenging activity, and pH-triggered drug release, enabling efficient pulmonary accumulation and sustained local retention. In vitro and in vivo ALI models demonstrated that pDA/Esc@ZIF-8 markedly alleviated lung inflammation, oxidative injury, and epithelial apoptosis, thereby preserving alveolar-capillary barrier integrity and improving respiratory function. Mechanistically, the therapeutic effects were closely associated with modulation of the PI3K/AKT/GSK3β signaling axis, leading to suppression of pro-inflammatory responses, attenuation of oxidative stress, and inhibition of mitochondria-dependent apoptotic pathways. Collectively, this multifunctional nanotherapeutic system integrates pulmonary priority accumulation, microenvironment-responsive release, and pathway-level regulation to interrupt the inflammation-oxidative stress-apoptosis cascade, offering a promising and translatable strategy for the treatment of ALI and related inflammatory lung diseases.