An enzyme-proof glycan glue for extracellular matrix to ameliorate intervertebral disc degeneration

Intervertebral disc degeneration (IDD) remains a global healthcare challenge. Here, by analyzing clinical samples, we discover the loss of milk fat globule-EGF factor 8 (MFG-E8) from the nucleus pulposus (NP) tissue-along with increased enzymatic breakdown of glycosaminoglycans (GAGs)-as an overlooked factor for IDD development. Repairing the degraded NP extracellular matrix (ECM) with a structurally-mimicking glycan glue to enrich MFG-E8 may counter the degeneration. Accordingly, we synthesize a glucomannan octanoate (GMOC) with robust resistance to ECM-cleaving enzymes, which forms assemblies with MFG-E8 to maintain a healthy NP cell phenotype. GMOC injected into the degenerated intervertebral disc enriches MFG-E8 in situ, leading to NP tissue regeneration in a rat and a rabbit model, which represent two clinical scenarios of pre-surgical intervention and post-surgical regeneration of IDD, respectively. In summary, we report enriching MFG-E8 in ECM with a glycan glue as a mechanism to promote NP regeneration for IDD treatment.