Bioactive Co-assembly of PSA/dit-VES Nanomicelles Orchestrates Macrophage Reprogramming for Acute Lung Injury Therapy

Acute lung injury (ALI) is a clinical emergency characterized by uncontrolled inflammatory cascades and oxidative stress, in which the dysregulation of macrophage polarization plays a pivotal role. Although flavonoid-based phytochemical anti-inflammatory agents hold promise for inhibiting NF-κB signaling and scavenging reactive oxygen species (ROS), their clinical efficacy is hampered by extremely poor aqueous solubility and a lack of tissue specificity. To address these challenges, this study developed a “bioactive co-assembly” nanomicelle platform (Qu@PSA-VES/diT-VES) based on polysialic acid (PSA) and a novel dimerized taurine-vitamin E succinate (diT-VES). Molecular docking simulations demonstrated that quercetin (Qu) exhibits an exceptionally high binding affinity for the VES hydrophobic core. Furthermore, the incorporation of diT-VES significantly enhanced the colloidal stability of the micelles through strengthened non-covalent interactions, effectively preventing disassembly during physiological circulation. Mechanistic investigations confirmed that hydrophobic interactions and hydrogen bonding are the core driving forces maintaining the structural integrity of the system. The carrier leverages PSA to specifically target the overexpressed Siglec-1 receptor on the surface of inflammatory macrophages, thereby mediating receptor-dependent endocytosis. Within the acidic and enzyme-enriched lysosomal environment, the micelles undergo pH/enzyme dual-responsive dissociation, facilitating the escape of the drug from the lysosomal barrier and its subsequent diffusion into the cytoplasm for pharmacological action. Additionally, the carrier components VES and taurine provide antioxidant and mitochondrial protection, respectively, synergizing with Qu to significantly induce the reprogramming of M1 macrophages toward the M2 phenotype in vitro . In a murine ALI model, the system demonstrated superior lung-targeting ability, significantly reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in bronchoalveolar lavage fluid and alleviating pulmonary edema and neutrophil infiltration. Experimental results indicated that under a lethal ALI challenge, the 72-hour survival rate of mice in the treatment group was significantly increased from 16.7% to 83.3%, while maintaining excellent in vivo biocompatibility. This integrated "targeting-stabilization-synergy" nanoplatform provides a promising translational strategy for the treatment of macrophage-driven inflammatory disorders.