Unmasking Chemokine‐Inducing Specificity in Oligosaccharide Biomaterial to Promote Hair Growth

Abstract Hair loss affects over 50 million people worldwide with limited therapeutic options. Despite evidence highlighting the vital role of local immune cells in regulating the life cycle of hair follicles (HFs), accurate regulation of immunocytes to directly promote hair growth remains unachieved. Here, inspired by the physiological feedback in the skin immunity to suppress microbe‐triggered inflammation, an oligosaccharide biomaterial with “unmasked” specific activity is developed to recruit regulatory T (T reg ) cells around HFs, leading to accelerated hair growth in mice. By processing the glucomannan polysaccharide via controllable enzymatic cleavage, a series of oligosaccharide fractions with more specific chemokine‐inducing functions is obtained. Notably, a hexasaccharide‐based fraction (OG6) stimulates macrophages to selectively express T reg ‐chemoattractant C‐C Motif Chemokine Ligand 5 (CCL5) through a mannose receptor‐mediated endocytosis and NOD1/2‐dependent signaling, as evidenced by molecular docking, inhibition assays, and a Foxp3‐reporter mouse model. Intradermal delivery of OG6 to the depilated mouse skin promotes T reg mobilization around HFs and stimulates de novo regeneration of robust hairs. This study demonstrates that unmasking precise immunomodulatory functions in oligosaccharides from their parental polysaccharide can potentially solve the long‐lasting dilemma with polysaccharide biomaterials that are widely renowned for versatile activities yet high heterogeneity, opening new avenues to designing glycan‐based therapeutic tools with improved specificity and safety.