Spatio-controlled sialic acid polymer molecular patterns for selective Siglecs modulation and cytokine storm...

Cytokine storm is a leading cause of mortality in severe infections and adverse responses during adoptive cell therapies. Leveraging multivalent sialic acids (SAs) and the specificity of the SA-Siglecs (SA-binding immunoglobulin-type lectins) axis to direct immune cell responses opens a compelling route to efficiently mitigate cytokine storms. However, the optimal configuration of multivalent SAs to maximize Siglec binding affinity and immune-directing activity has yet to be elucidated. Herein, we report Sialic Acid Polymer Molecular Patterns (SPMPs), a class of synthetic macromolecular immunomodulators engineered with precise control over polymer backbone conformation, pendant SA spacing, and branching topology. This molecular pattern recreates the hierarchical multivalency of natural glycans while exploiting the modularity of polymer chemistry and molecular controlled SA patterns. Super-resolution fluorescence microscopy and single-molecule spectroscopy confirm structure-specific sialic acid patterns promote Siglec-E clustering and high-affinity engagement, triggering potent inhibitory signaling and reshaping innate immune cell functions to abrogate cytokine storms. These pattern-encoded macromolecules establish a new paradigm for precise immune modulation and offer a framework for materials-based interventions in inflammatory disorders.