Multienzyme active melanin nanodots for antioxidant-immunomodulatory therapy of hyperoxia lung injury

Supraphysiological oxygen is the most conventional method of treating patients with acute respiratory failure, but prolonged exposure to hyperoxia generates large amounts of reactive oxygen species (ROS) in the lungs, leading to hyperoxia lung injury (HLI). Nevertheless, there is no safe and effective prevention strategy. Herein, multienzyme active melanin nanodots were developed as an antioxidant-immunomodulatory defense nanoplatform for the treatment of HLI. The prepared nanodots are about 4 nm in size and are mainly composed of carbon, nitrogen and oxygen elements with high stability and multi-enzymatic activity for scavenging various reactive oxygen and reactive nitrogen radicals. Cellular experiments showed that melanin nanodots increased cell viability and ameliorated hyperoxia-induced morphological changes, mitochondrial damage and apoptosis. Meanwhile, by activating the Nrf2/Keap1/HO-1 signaling pathway, the treatment of melanin nanodots significantly inhibited the overproduction of ROS, reduced malondialdehyde, and increased the endogenous antioxidant enzyme activity in BEAS-2B cells. Interestingly, the antioxidant properties of melanin nanodots indirectly promoted the phenotypic shift of macrophages, and reduced hyperoxia-induced inflammatory responses in the damaged environment. In vivo NIR-II fluorescence imaging confirms the high retention of nanodots in the lungs and low accumulation in other major organs after inhalation administration, as well as the high biosafety of the melanin nanodots as they are metabolized out of the body over time via the liver and intestines. In addition, the melanin nanodots exhibited satisfactory antioxidant protection and inhibition of inflammatory cell infiltration in the lungs of HLI mouse models. Therefore, the melanin nanodots provide a potential and effective strategy for the treatment of HLI, showing great promise for application.