ROS-responsive resveratrol-loaded cyclodextrin nanomicelles reduce inflammatory osteolysis

Bone loss in inflammatory disorders such as osteomyelitis, septic arthritis, and periodontitis is caused by excessive osteoclastic activity. Meanwhile, reactive oxygen species (ROS) have been identified as contributors to osteoclast differentiation, and the application of ROS scavengers has emerged as a promising strategy to protect against bone loss. Recently, resveratrol (RSV), a polyphenolic phytoalexin, has been demonstrated to inhibit osteoclastogenesis by scavenging ROS; however, the application of RSV as an antioxidant is limited by its low water solubility, structural instability, and short elimination half-life. In this study, we developed a PEGylated cyclodextrin (CD)-based nanoplatform (PCP) for local delivery of RSV as nanomicelles (RSV-NMs). In addition, polymer functionalization with phenylboronic acid ester in RSV-NMs successfully achieved ROS-responsive release of RSV. The RSV-NMs in a well-dispersed state possessed good biocompatibility as well as improved solubility and stability compared with RSV compound. In vitro, RSV-NMs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and suppressed F-actin (filamentous actin) ring formation. Additionally, the mRNA expressions of osteoclastic marker genes, including matrix metalloprotein-9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), TRAP, and cathepsin K, were consequently downregulated in the presence of RSV-NMs. In vivo, RSV-NMs provided protection against LPS-induced bone destruction, as evidenced by a decreased number of osteoclasts, increased bone density, and reduced area of bone resorption. Taken together, these results indicate that our ROS-responsive RSV-NMs can be employed as a potential therapeutic agent for the treatment of inflammatory osteolysis.