Inflammatory microenvironment-responsive nanomicelles for acute lung injury therapy: ROS-scavenging and macrophage repolarization

The pathogenesis of acute lung injury (ALI) is characterized by an uncontrolled inflammatory response, marked by excessive production of reactive oxygen species (ROS) and the infiltration of inflammatory cells, particularly macrophages, which play a pivotal role in disease progression. The synergistic effect of ROS scavenging and macrophage repolarization provides a promising strategy for effective ALI treatment. Herein, we developed a novel type of self-assembling nanomicelles, which were composed of poly-L-glutamic acid (PLG) and 4-Hydroxymethyl phenylboronic acid (PBA). The nanomicelles (PPDex micelles) had a high drug-loading capacity for dexamethasone (Dex) based on boronic ester bonds, which exhibited reversible cleavage under inflammatory conditions characterized by elevated levels of ROS or decreased pH values. These PPDex micelles revealed rapid drug-responsive release behavior in the inflammatory environment, and in vivo studies demonstrated their efficacy in modulating cytokines, inhibiting oxidative stress, and promoting macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, which ultimately suppressed the progression of ALI. Moreover, the PPDex micelles had the effective ability to effectively suppress the NF-кB and ROS/NLRP3 inflammatory pathways. Therefore, this study presented a novel and potent therapeutic strategy for ALI treatment, which could promote the clinical application of polymer nanomicelles in the treatment of ALI. Schematic illustration of the preparation of inflammatory microenvironment-responsive PPDex micelles and their therapeutic effect for ALI in vivo .