Liposomal Quercetin-Loaded Biomimetic Scaffolds Manage Mechanical Overload in Maxillofacial Regeneration by Stabilizing the β-Actin/YAP Mechanosensing Axis

Critical-sized maxillofacial bone defects are frequently exposed to pathological mechanical overload (MO), which disrupts cellular mechanosensing and compromises bone regeneration. However, strategies that protect osteogenic cells from overload-induced mechanobiological dysfunction remain limited. Here, we develop a biomimetic scaffold incorporating liposomal quercetin (LQ) into a Collagen/silk fibroin/nano-hydroxyapatite matrix (LQ-CSH) to restore osteoblast function under pathological loading conditions. MO induces cytoskeletal disorganization and oxidative stress, leading to inactivation of the mechanotransducer Yes-associated protein (YAP). LQ treatment markedly reduces intracellular oxidative stress, preserves β-actin cytoskeletal integrity, and restores YAP nuclear localization, thereby rescuing osteoblast proliferation and osteogenic differentiation. Pharmacological inhibition of β-actin polymerization or YAP signaling abolishes these protective effects, confirming the critical role of the β-actin/YAP mechanosensing axis. In a rabbit mandibular critical-sized defect model with simulated occlusal overload, LQ-CSH scaffolds significantly enhance bone regeneration, improving bone volume fraction, mineral density, and trabecular architecture compared with control scaffolds. These findings highlight a mechanochemical strategy that protects osteogenic cells from overload-induced dysfunction and provide a promising therapeutic approach for bone regeneration in mechanically hostile environments.