Biocompatible and size-dependent melanin-like nanocapsules for efficient therapy in hyperoxia-induced acute lung injury.

Hyperoxia-induced acute lung injury (HALI) is a serious pulmonary disease, and its therapeutic effect is greatly limited by disordered oxidative stress microenvironment. Safe and efficient antioxidant-immunomodulatory therapy may be a promising strategy to maintain redox homeostasis in HALI. Herein, a novel therapeutic strategy (PCT) composed size-dependent melanin-like polydopamine nanocapsules (PC) and IKK-2 inhibitor TPCA-1 is developed to alleviate HALI. By flexibly tuning the size of nanocapsules, the lung-to-liver ratio could be finely optimized, which facilitates to delivery adequate dose of TPCA-1 to pulmonary lesions and improve the bioavailability. Notably, these nanocapsules exhibit superior biosafety in vitro and in vivo. The selected PCT sharply scavenges intracellular reactive oxygen species (ROS) and protects mitochondrial function, subsequently reprogramming the repolarization of macrophages. Moreover, injection of PCT eliminates elevated ROS and oxidative stress products against the redox imbalance in HALI mice. Mechanistically, benefiting from much ROS depletion, PCT plays a positive role in inhibiting immune cell infiltration, down-regulating multiple inflammatory factors, and promoting macrophage polarization toward anti-inflammatory M2 phenotype through activating the Keap-1/Nrf2 pathway, thus remarkably breaking the vicious cycle of inflammation and oxidative stress in HALI. Overall, these findings provide a secure and effective therapy combining antioxidation and immunoregulation for HALI and other pulmonary diseases.