Quercetin-derived carbon dots-modified ZIF-8 and M2 macrophage-derived migrasomes-functionalized microenvironment-responsive nanocomposite hydrogel for osteoporotic bone defects regeneration

The impaired regenerative capacity of osteoporotic individuals poses a significant challenge to the repair of bone defects. In the osteoporotic microenvironment, low pH, excessive reactive oxygen species (ROS), and chronic inflammation create a self-perpetuating vicious cycle that impedes healing. However, conventional therapies fail to sustainably improve the damaged microenvironment. Here, a pH/ROS dual responsive nanocomposite hydrogel (Z-QCDs@M2-Migs@OHA-PP) was developed based on oxidized hyaluronic acid (OHA), phenylboronic acid-grafted ε-polylysine (PP), quercetin-derived carbon dots (QCDs) loaded ZIF-8 (Z-QCDs) and M2 macrophage-derived migrasomes (M2-Migs), which possesses intrinsic antioxidant and osteogenic differentiation-promoting capabilities. Due to the presence of dynamic. Schiff base bonds and boronate bonds, the hydrogel exhibited injectability and pH/ROS dual responsiveness. OHA-PP releases Z-QCDs and M2-Migs on demand in response to changes in pH and ROS levels. Z-QCDs exhibit strong antioxidant and nanozyme activity, capable of scavenging ROS, suppressing inflammatory responses, and promoting M2 macrophage polarization. Furthermore, the introduction of M2-Migs as an osteogenic activator further enhances the capacity for osteogenic differentiation. Transcriptomic and Western blot analyses revealed that the hydrogel promotes osteogenic differentiation by activating the PI3K-AKT signaling pathway. In a mouse osteoporotic bone defect model, the nanocomposite hydrogel effectively inhibited ferroptosis, modulated inflammation, and promoted new bone formation. Therefore, this hydrogel system, which combines therapeutic rationale with microenvironmental regulation, offers a promising strategy for the regeneration of osteoporotic bone defects.