Hydrogel-guided benzoylpaeoniflorin delivery rebalances Nrf2/NF-κB signaling for osteoarthritis therapy

Osteoarthritis (OA) is a prevalent degenerative joint disease driven by intertwined chondrocyte apoptosis, inflammatory activation, and extracellular matrix (ECM) catabolism. Disease-modifying pharmacological options remain limited, and intra-articular small-molecule therapy is often constrained by rapid clearance from the joint cavity. Here, we investigated benzoylpaeoniflorin (BPF), a bioactive monoterpenoid glycoside from Paeonia lactiflora, and developed a BPF-loaded injectable HDPB hydrogel for local OA treatment. In IL-1β-stimulated primary chondrocytes, BPF reduced apoptosis-related proteins, inflammatory mediators, and matrix-degrading enzymes while restoring ECM anabolic markers. Mechanistically, BPF promoted Nrf2 activation and suppressed NF-κB signaling, whereas Nrf2 knockdown weakened these chondroprotective effects. In destabilization of the medial meniscus (DMM)-induced OA mice, free BPF alleviated cartilage degeneration and inflammatory activation. The HDPB hydrogel displayed a porous architecture, tissue adhesion, shear-thinning injectability, and self-healing behavior, enabling sustained local delivery of BPF. Compared with free BPF, intra-articular HDPB treatment further preserved cartilage structure, reduced iNOS and cleaved caspase-3 expression, and restored collagen II. These findings identify BPF as an Nrf2/NF-κB-modulating chondroprotective agent and support HDPB (HA-HAD-HAP-BPF) hydrogel-mediated delivery as a promising local therapeutic strategy for OA.