Spontaneous Inflammation Resolution Inspired Nanoparticles Promote Neutrophil Apoptosis and Macrophage Efferocytosis for Acute Respiratory Distress Syndrome Treatment

Abstract During acute respiratory distress syndrome (ARDS), delayed apoptosis of neutrophils and impaired efferocytosis of macrophages constitute two critical limiting steps, leading to secondary inflammatory storm and posing a significant threat to human health. However, due to the failure of previous single target‐centric treatments to effectively address these two limiting steps in controlling the inflammatory storm, no available therapies are approved for ARDS treatment. Herein, inspired by spontaneous inflammation resolution, two kinds of Apoptosis and Efferocytosis Restored Nanoparticles (AER NPs) are proposed to overcome these two limiting steps for counteracting severe inflammatory storm. For the first limiting step, neutrophil‐targeted apoptosis‐restored nanoparticles (AR NPs) accelerated the programmed apoptosis of inflammatory neutrophils. The resolution of the first limiting step facilitated the accumulation of macrophage‐targeted and efferocytosis‐restored nanoparticles (ER NPs), thereby restoring macrophage efferocytosis and alleviating the second limiting step. The results indicated that after sequential treatment with AER NPs, recruited neutrophils decreased to 13.86%, and macrophage efferocytosis increased to 563.24%. AER NPs promoted inflammation resolution and established a self‐healing virtuous loop by addressing the two limiting steps, ultimately effectively treating ARDS. This work suggests that a strategy inspired by inflammation resolution holds promise as a potential approach for advancing inflammation therapy.