*Data embargoed until publication of related article or up to no more than 1 year from data upload.*\ Abstract: Glycosylation regulates immune and neural functions within the central nervous system (CNS) but its use in biomaterial therapies remains limited due to its structural and biochemical complexity. Among glycans sialic acids—particularly polysialic acid (PSA) comprising α28-linked Neu5Ac residues—exhibit potent immunomodulation through interactions with inhibitory Siglec receptors on immune cells. To harness this potential we engineered an injectable microporous annealed particle (MAP) scaffold presenting PSA covalently via its reducing end recapitulating physiological glycan orientation (MAP-PSA). This biomimetic platform demonstrated robust mechanical integrity stable PSA immobilization and enzymatic resilience. Systematic screening of sialic acid derivatives identified PSA as uniquely effective at inducing anti-inflammatory polarization of bone marrow-derived macrophages (BMDMs). In vivo using stroke as a model of CNS injury MAP-PSA induced a differential immune response compared to MAP alone. MAP-PSA significantly attenuated neutrophil infiltration and inflammatory activation while enhancing reparative macrophage and microglial phenotypes. These immune responses persisted into subacute stages resulting in sustained inflammation reduction and improved microglial homeostasis. These results demonstrate for the first time that PSA anchored to MAP though its reducing end can be used as an anti-inflammatory bioactive signal in vitro and in vivo.
