Bioactive co-assembly of PSA/diT-VES nanomicelles orchestrates macrophage reprogramming for acute lung injury therapy.

Acute lung injury (ALI) is characterized by uncontrolled inflammation and oxidative stress, driven largely by macrophage dysregulation. Despite their anti-inflammatory potential, flavonoids like quercetin (Qu) are limited by poor solubility and systemic toxicity. 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. Hydrophobic interactions and hydrogen bonding were identified as the primary driving forces for micellar stability. 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-h 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.