Matrix-Metalloproteinase-Responsive Brain-Derived Neurotrophic Factor for Spinal Cord Injury Repair

Abstract

Brain-derived neurotrophic factor (BDNF) plays a vital role in supporting neuronal survival, differentiation, and promoting synaptogenesis, thereby facilitating synaptic plasticity in the central nervous system. Administration of exogenous BDNF is a crucial approach for treating central nervous system injuries. However, the inability of sustained drug release to match disease activity often leads to insufficient drug accumulation in the injured area (ineffectiveness) and severe side effects induced by the drug (toxicity). Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are typically upregulated after tissue damage, and their upregulated expression levels represent the degree of disease activity. In this study, we utilized bioengineering techniques to prepare a BDNF that can specifically bind to collagen and be released in response to MMP substrate cleavage (collagen binding domain tissue inhibitor of matrix metalloproteinases brain-derived neurotrophic factor, CBD-TIMP-BDNF). We verified the ability of CBD-BDNF and CBD-TIMP-BDNF to specifically bind to collagen through collagen binding experiments, examined the characteristics of CBD-TIMP-BDNF in response to MMP-2 to release BDNF, and detected the biological activities of both recombinant proteins. The results demonstrated that the established microenvironment-controlled BDNF release system can respond to MMP-2 to release BDNF. The recombinant proteins CBD-BDNF and CBD-TIMP-BDNF exhibited similar biological activities to the BDNF standard. Targeting the upregulated expression of MMPs after spinal cord injury as a trigger for drug release, it is expected to achieve on-demand release of BDNF in response to the severity of the disease.