A Glycan-Based Ligand Panel for Phenotypic Profiling and Selective Immunomodulation of Alveolar Macrophage

The balance of alveolar macrophage (AM) polarization is severely disrupted in chronic in-flammatory diseases like bronchiectasis, where a persistent pro-inflammatory (M1) phe-notype perpetuates inflammation. To address this, we developed a high-throughput plat-form using a series of synthetic glycoligands (L1-L5) on a polyethyleneimine (PEI) scaf-fold. These ligands, which have varying affinities for macrophage lectin-like receptors, were used for phenotypic "fingerprinting" of AM subpopulations from pediatric bronchi-ectasis patients and a healthy control. Analysis of bronchoalveolar lavage fluid (BALF) revealed a pathogenic, M1-dominant profile (55% M1) in patients, confirming a state of chronic inflammation, which starkly contrasted with the quiescent, M0-dominant profile in the healthy control. We then leveraged this platform for targeted immunomodulation, using a drug-ligand conjugate to steer the dysregulated macrophage population toward a healthy state. The most potent conjugate, Dox-L5, dramatically suppressed the pathogenic M1 population (from 55% to 16%). This M1 suppression was accompanied by a signifi-cant shift toward the M2a (tissue-repair) phenotype and the emergence of a quiescent M0-like population, effectively remodeling the AM profile. This work validates a gly-can-based platform for both diagnosing and correcting pathological macrophage imbal-ances. Our targeted approach offers a precise strategy to resolve chronic inflammation in bronchiectasis by suppressing M1 macrophages and promoting a pro-resolving M0/M2 phenotype, thereby restoring lung homeostasis.