Pulmonary delivery of dynamic size-switching microspheres for regulation of neutrophils and macrophages in the acute respiratory distress syndrome

Modulation of the interaction between neutrophils and macrophages is pivotal for controlling the inflammatory response in acute respiratory distress syndrome (ARDS). To enhance pulmonary drug deposition efficiency and simultaneously regulate macrophages and neutrophils, dynamic size-switching microsphere complexes (DNMP) were synthesized based on a double emulsion formulation strategy, utilizing acetalated dextran (Ac-Dextran) as the matrix material and co-encapsulated roflumilast-loaded albumin nanoparticles (BNP) and dexamethasone (DEX). DNMP exhibited high uniformity and encapsulation efficiency. Upon pulmonary administration, the micron-sized DNMP demonstrated remarkable deposition efficiency in the lungs, with a pulmonary retention time exceeding 48 h. Within the acidic microenvironment of inflamed lung, DNMP rapidly disintegrated, thereby releasing the co-encapsulated BNP and DEX. The BNP exhibited specific targeting towards neutrophils, subsequently releasing roflumilast to exert potent anti-inflammatory effects. Meanwhile, DEX modulated macrophage polarization and the overall inflammatory microenvironment, thereby contributing to a comprehensive and synergistic therapeutic strategy for mitigating pulmonary inflammation. As expected, DNMP alleviated lung injury by reducing neutrophil infiltration, decreasing the proportion of pro-inflammatory M1-like macrophages, suppressing inflammatory cytokine and ROS levels, and inhibiting neutrophil extracellular traps (NETs) formation. This innovative acid-responsive dual-drug delivery system provided a promising therapeutic strategy for ARDS.