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Acute lung injury (ALI) is associated with excessive inflammatory response, leading to acute respiratory distress syndrome (ARDS) without timely treatment. A fewer effective drugs are available currently to treat the ALI/ARDS. Herein, a therapeutic nanoplatform with reactive oxygen species (ROS)-responsiveness was developed for the regulation of inflammation. Dexamethasone acetate (Dex) was encapsulated into poly(thioketal) polymers to form polymeric nanoparticles (NPs) (PTKNPs@Dex). The NPs were composed of poly(1,4-phenyleneacetonedimethylene thioketal) (PPADT) and polythioketal urethane (PTKU), in which the thioketal bonds could be cleaved by the high level of ROS at the ALI site. The PTKNPs@Dex could accumulate in the pulmonary inflammatory sites and release the encapsulated payloads rapidly, leading to the decreased ROS level, less generation of pro-inflammatory cytokines, and reduced lung injury and mortality of mice. RNA sequencing (RNA-seq) analysis showed that the therapeutic efficacy of the NPs was associated with the modulation of many immune and inflammation-linked pathways. These findings provide a newly developed nanoplatform for the efficient treatment of ALI/ARDS.