Paeoniflorin-loaded MBG Nanogel Alleviates Oxidative Microenvironment and Reinforces Subchondral Bone Regeneration for Osteoarthritis Treatment

Abstract Osteoarthritis (OA) involves synergistic pathological changes in both cartilage degradation and subchondral bone remodeling due to oxidative stress, yet current therapies typically target these processes separately. To address this limitation, we developed a dual-functional nanogel (MBG@Pae@HA) by conjugating hyaluronic acid (HA) and paeoniflorin (Pae) to mesoporous bioactive glass nanoparticles via amide bonding and non-covalent interactions, respectively. Leveraging the inherent hydrophilicity of HA, MBG@Pae@HA spontaneously forms nanogels and shows enhanced adhesion force which ensure extended Pae and bioactive ions release in the OA microenvironment. MBG@Pae@HA exhibits potent reactive oxygen species (ROS)-scavenging capacity, contributing to the homeostatic balance between cartilage matrix anabolism and catabolism. Transcriptomic analysis revealed that MBG@Pae@HA treatment reactivates chondrocyte function through activating the cAMP/PKA/CREB antioxidant pathway. Furthermore, with controlled release of Pae and bioactive components (including Ca ions, Si ions, and PO43-) it significantly promotes osteogenesis of bone stem cells. Medial meniscotibial ligament (DMM) model demonstrated the dual therapeutic efficacy of MBG@Pae@HA nanogel with histological and micro-CT analyses confirming concurrent protection against cartilage degradation and enhancement of subchondral bone regeneration. By simultaneously addressing both major pathological features of OA through microenvironment remodeling and prolonged drug delivery, this HA-functionalized and Pae-loaded nanogel represents a significant advance in OA treatment strategies, offering a comprehensive approach to halt disease progression and promote joint repair.