Treatment of Heterotopic Ossification via Inhibiting the MMP-2/CDH5 Axis through Oral Delivery of Network Pharmacology-Predicted Chinese Medicine

Heterotopic ossification (HO) is characterized by ectopic bone formation in soft tissues such as tendons, with an incidence exceeding 30% in high-risk populations. Currently, no targeted therapeutic options are available. In this study, matrix metalloproteinase-2 (MMP-2) was identified as a critical promoter of HO by mediating the degradation of vascular endothelial cadherin 5 (CDH5), thereby enhancing vascular permeability and facilitating inflammatory cell infiltration. Through network pharmacology analysis, Forsythoside A (FA), a compound derived from the traditional Chinese medicine Forsythia , was predicted to act as a potential MMP-2 inhibitor. However, the clinical application of FA is hindered by its narrow therapeutic window. To overcome this limitation, we developed an intestinal enzyme-responsive hydrogel (FA@SD-hydrogel) for targeted delivery of FA. This delivery system significantly improved the bioavailability of FA and enabled sustained release, thereby reducing the required dosage and associated toxicity. Comprehensive in vivo and in vitro experiments demonstrated that FA@SD-hydrogel achieved superior therapeutic efficacy against HO with reduced toxicity. By inhibiting MMP-2, the hydrogel effectively suppressed ectopic bone formation, reduced local vascular permeability, and reversed the inflammatory microenvironment driven by M1 macrophages, ultimately reprogramming the osteogenic niche. Together, these findings underscore the critical role of the MMP-2/CDH5 axis in HO pathogenesis and establish a targeted therapeutic strategy via FA@SD-hydrogel through the integration of network pharmacology and biomaterial engineering.