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Inflammatory microenvironment-responsive nanomicelles for acute lung injury therapy: ROS-scavenging and macrophage
Chang Liu1, Rui Zhou1, Baiqiao Chen1
1College of Basic Medical Sciences, The Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
Abstract:
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.
Insights
This study presents novel nanomicelles that deliver dexamethasone to treat acute lung injury (ALI). These micelles reduce inflammation and oxidative stress by scavenging reactive oxygen species (ROS) and reprogramming macrophages.
Area of Science:
- Biomaterials Science
- Nanomedicine
- Pulmonary Medicine
Background:
- Acute lung injury (ALI) pathogenesis involves uncontrolled inflammation, excessive reactive oxygen species (ROS), and macrophage infiltration.
- Targeted therapies are needed to address ROS and modulate macrophage phenotypes for effective ALI treatment.
Purpose of the Study:
- To develop and evaluate novel self-assembling nanomicelles for targeted drug delivery in ALI.
- To investigate the therapeutic potential of these nanomicelles in scavenging ROS and repolarizing macrophages.
Main Methods:
- Fabrication of poly-L-glutamic acid (PLG) and 4-Hydroxymethyl phenylboronic acid (PBA) based nanomicelles loaded with dexamethasone (Dex).
- Assessment of drug release kinetics under inflammatory conditions (elevated ROS, decreased pH).
- In vivo evaluation of nanomicelle efficacy in modulating cytokines, inhibiting oxidative stress, and promoting M2 macrophage polarization.
Main Results:
- The developed PPDex nanomicelles demonstrated high drug-loading capacity and rapid, responsive drug release in inflammatory environments.
- In vivo studies confirmed suppression of ALI progression by modulating cytokines, reducing oxidative stress, and shifting macrophages from M1 to M2 phenotype.
- Effective inhibition of NF-κB and ROS/NLRP3 inflammatory pathways was observed.
Conclusions:
- The novel PPDex nanomicelles offer a potent therapeutic strategy for ALI by combining ROS scavenging and macrophage repolarization.
- This approach holds promise for the clinical application of polymer nanomicelles in treating ALI and related inflammatory lung diseases.
