Injectable Ca(2+)/Sr(2+)-crosslinked hydrogel with sustained release of LGK-974 for cartilage repair and osteoarthritis prevention via alleviating inflammatory microenvironment.

Cartilage injury would trigger a chronic inflammatory microenvironment that disrupts tissue regeneration and accelerates the onset of osteoarthritis (OA). However, current treatments primarily focus on the symptomatic relief of OA but fail to address the underlying pathophysiological issues. Herein, we developed an injectable Ca(2+)/Sr(2+)-crosslinked hydrogel incorporating LGK-974/polydopamine nanoparticles for immune regulation and cartilage regeneration. Given the pivotal role of Wnt signaling activation in OA, LGK-974, a Wnt pathway inhibitor targeting the key upstream component (Porcupine) was first integrated for OA prevention. It came out that Sr(2+) optimized the physical properties of the modified hydrogel and synergistically released with LGK-974, which potently suppressed the Wnt/β-catenin pathway, effectively promoted M2 macrophage polarization, reactive oxygen species (ROS) scavenging, chondrocytes proliferation and extracellular matrix (ECM) secretion. In vivo studies further confirmed that the hydrogel significantly promoted cartilage repair and stimulated ECM regeneration. Building on the pathogenesis of OA, this study suggests that the novel injectable hydrogel holds great promise as an effective therapeutic strategy for promoting cartilage repair and preventing OA progression through minimally invasive intervention.