Targeting the lactate/P300/H3K18la epigenetic pathway with a mechanoadaptive biomimetic hydrogel to suppress traumatic tendon heterotopic ossification

Traumatic heterotopic ossification (HO) is a debilitating complication of tendon injury, yet its pathogenic mechanisms remain elusive and effective preventive strategies are lacking. Here, we identify a glycometabolic-epigenetic axis that drives HO progression. Single-cell profiling and functional analyses reveal that hypoxic chondrocytes undergo glycolytic reprogramming, leading to lactate accumulation and transfer into tendon-derived mesenchymal stem cells (TD-MSCs) through MCT1. This metabolic coupling promotes P300-dependent histone H3 lysine 18 lactylation (H3K18la), activating osteogenic programs characterized by Col6a1 , Zhx3 , Lox and Vdr expression and thereby facilitating pathological endochondral ossification. Guided by this mechanism, we develop a tendon-adhesive hydrogel (GelHA-A485@Exos) that integrates mechanical repair with targeted epigenetic modulation. MSC-derived exosomes enable localized delivery of the P300 inhibitor A485, suppressing H3K18la and aberrant osteogenic activation, while the hydrogel scaffold enhances tendon regeneration. In vivo and in vitro studies demonstrate that GelHA-A485@Exos promotes tendon healing while preventing HO formation. Our findings establish metabolic-epigenetic communication as a central regulator of traumatic HO and provide a translational therapeutic strategy for its clinical prevention.