Prolonged resident nanoparticles effectively treat acute lung injury via the selective upregulation of intracellular hydrogen peroxide.

Selective modulation of the types of reactive oxygen species (ROS) for the treatment of acute lung injury (ALI) has not been tackled, whereas the usually applied hydrophobic nanoparticles (NPs) are easily excreted and metabolized. Herein, a zwitterionic-segment containing polyurethane was synthesized to formulate into Pazopanib (Pazo)-loaded NPs (PUSB@Pazo NPs), which had the ability to selectively enhance the expression of H 2 O 2 but suppress other types of ROS, and achieved long retention in lung and thereby improved treatment efficacy. The zwitterionic group of PUSB effectively decreased the clearance rate of PUSB@Pazo NPs in vivo , and prolonged their resident time in lung post inhalation up to 48 h. The increase of local H 2 O 2 concentration decreased the permeability of lung epithelial cells, accompanied by the significantly reduced tissue edema and inflammatory cell recruitment. The system also reduced the expression of various inflammatory factors, revealing its effective and promising treatment for ALI. [Display omitted] • Zwitterionic ROS-responsive polyurethane (PUSB) was synthesized. • PUSB@Pazo NPs had longer residence in alveoli and selectively enhanced H 2 O 2 secretion. • Cytokine storm in ALI was suppressed with downregulated inflammatory factors. • New insights for delivery of therapeutic aerosols with significance in ALI therapy. [ABSTRACT FROM AUTHOR]