Multivalent effects of heptamannosylated β-cyclodextrins on macrophage polarization to accelerate wound healing

Macrophages have high plasticity and heterogeneity, and can suppress or mediate inflammation, depending on their cytokine secretion and phenotype. Regulating macrophage polarization into its M2 phenotype has a remarkable effect on inflammatory inhibition, inducing the regeneration of injured tissues. Here, we synthesized two heptamannosylated β-cyclodextrin derivatives (CD-Man7 and C₃-CD-Man7) and demonstrated that their multivalent mannose ligands could induce M2 macrophage polarization to accelerate wound healing. Unlike hydrophilic CD-Man7, amphiphilic C₃-CD-Man7 can self-assemble to form nanoparticles (CD-Man-NPs) in aqueous solution. Further, in vitro results confirmed that multivalent mannose ligands of either CD-Man7 or CD-Man-NPs stimulated RAW264.7 macrophages to differentiate into the M2 phenotype, which promoted fibroblast migration via a paracrine mechanism. In vivo results confirmed that both CD-Man7 and CD-Man-NPs reduced the inflammatory response in wound tissue and accelerated wound healing. The present study demonstrates multivalent effects of CD-Man7 and CD-Man-NPs on M2 macrophage polarization, indicating the therapeutic potential of these β-cyclodextrin glycoconjugates in the treatment of inflammatory diseases and wound healing.