MAP Crosslinker Chirality Regulates Macrophage Polarization Through MD-2 Engagement and Enables Tunable Immunomodulation Through Novel Peptide Design.

Authors

Alejandra Suarez-Arnedo, Jeremy L Thomas, Yining Liu, Pablo Cordero-Alvarado, Amy Kim, April Chavez Espinoza, Leica Harvey, Koravit Poysungnoen, Fayanne Lin, Zhiyou Ye, Tatiana Segura

Published in

Advanced healthcare materials. Pages e71572. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

Microporous annealed particle (MAP) scaffolds are injectable hydrogel biomaterials that promote tissue regeneration by enabling rapid cell infiltration and presenting reparative cues. Previous work showed that substituting L- with D-chiral residues in matrix metalloproteinase (MMP)-degradable crosslinkers induces adaptive immune-mediated skin regeneration and balanced macrophage responses in vivo, but the underlying mechanisms remain unclear. Here, we identify myeloid differentiation factor 2 (MD-2)-associated TLR4 signaling as a key mechanistic contributor to macrophage polarization driven by crosslinker chirality in MAP scaffolds. Macrophages cultured in D-chiral MAP (DMAP) scaffolds exhibited reduced iNOS, CD86, and TNF-α expression and shifted from an M1-like state toward M0-like phenotypes compared to L-chiral MAP (LMAP) and 2D controls. Competitive inhibition with soluble D-chiral MMP crosslinker peptide (DMMP) partially restored M1 activation, implicating direct peptide-macrophage interactions. Docking and surface plasmon resonance (SPR) analyses revealed higher-affinity binding of DMMP to MD-2 relative to L-chiral peptides. Accordingly, DMAP altered TLR4/MD-2 trafficking and attenuated endocytosis-dependent signaling. Engineering a second D-peptide crosslinker with enhanced MD-2 affinity (DMMP2) reduced inflammatory markers and promoted regenerative macrophage polarization. Together, these results establish peptide chirality as a tunable design parameter for modulating TLR4/MD-2 signaling and engineering immunomodulatory MAP scaffolds.

PMID:
42596107
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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