Injectable bioresponsive nanocomposite hydrogels for ROS scavenging and immunomodulation to accelerate diabetic bone repair

A bioresponsive multifunctional composite system is constituted by the HHPP hydrogel, which integrates PBA-OHA and PVA with composite nanoparticles (RB-HNTs). • For the first time, regaloside B (RB) within the hydrogel is found to exert anti-inflammatory effects through inhibition of the AGE-RAGE signaling pathway. • By combining RB and bioactive silicon, the hydrogel restores mitochondrial membrane potential and enhances the osteogenic differentiation of BMSCs. • In vivo, the hydrogel accelerates diabetic bone defect healing by alleviating ROS-induced inflammation and promoting osteogenesis. Repairing diabetic bone defects remains challenging due to hyperglycemia, oxidative stress, chronic inflammation, and metabolic dysfunction. To address this, we developed a bioresponsive multifunctional composite hydrogel (HHPP) based on phenylboronic acid-modified oxidized hyaluronic acid (OHA-PBA) and polyvinyl alcohol (PVA), encapsulating composite nanoparticles (RB-HNTs). In the diabetic microenvironment, regaloside B (RB) released from the hydrogel scavenges reactive oxygen species (ROS), promotes M1-to-M2 macrophage polarization, and alleviates inflammation. Network pharmacology and western blotting revealed that this anti-inflammatory effect is associated with the AGE-RAGE signaling pathway. RB also restores mitochondrial function and reverses metabolic disorders in bone marrow mesenchymal stem cells (BMSCs) under diabetic conditions, while synergizing with bioactive silicon released from HNTs to enhance BMSC osteogenesis. In vivo, HHPP significantly reduces glucose-ROS-induced inflammation and promotes bone formation, accelerating diabetic bone defect healing. This study offers a viable strategy for treating diabetic bone defects. Schematic illustration of the fabrication of HHPP hydrogel and its application. Download: Download high-res image (165KB) Download: Download full-size image