Self-Assembled Carrier Free Oligomeric Proanthocyanidin/Tetrandrine Nanoparticles Ameliorate Osteoarthritis via Anti-Inflammatory and Anti-Ferroptotic Pathways

Chengyuan Xing,1,* Yu Wu,1,* Yao Huang,1 Weijie Li,1 Xie Wang,2 Huikun Chen1 1Institute of Sports Medicine and Health, Sports Medicine Key Laboratory of Sichuan Province, Key Laboratory of Sports Medicine, General Administration of Sport of China, Chengdu Sport University, Chengdu, Sichuan, People’s Republic of China; 2Department of Anesthesiology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xie Wang, Email [email protected] Huikun Chen, Email [email protected]: This study aims to design and characterize Oligomeric Proanthocyanidin-Tetrandrine nanoparticles (OPC-Tet NPs) in alleviating progress of osteoarthritis (OA) by anti-inflammatory and anti-ferroptosis mechanism.Methods: A carrier-free drug delivery system (DDS) has been designed based on OPC and Tet with the unification of medicines and excipients. In vitro studies have evaluated biosafety, cellular internalization, suppression of oxidative stress, and maintaining iron homeostasis in RAW 264.7 cells. The treatment efficacy and mechanism were investigated by using the papain-induced OA mouse model.Results: OPC and Tet were successfully self-assembled into NPs with a particle size of 153 nm approximately, exhibiting a spherical morphology, and narrow size distribution. In vitro results indicated that OPC-Tet NPs exhibit good biocompatibility with 78.4% cell viability at a concentration of 40 μg/mL. The results from micro-CT and pathological staining demonstrate that OPC-Tet NPs can effectively improve bone volume fraction (BV/TV [%]) by 30.5% compared to model group (P < 0.001). Furthermore, IHC experiments showed that OPC-Tet NPs could mediate inflammation and ferroptosis to manage OA.Conclusion: In summary, our results demonstrate OPC-Tet NPs show good biocompatibility, and treatment effect. The treatment mechanism of anti-inflammation and anti-ferroptosis were also verified. The current research not only offers a new strategy to manage OA but also provides more possibilities for potential application of natural products. Keywords: osteoarthritis, natural products, oligomeric proanthocyanidins, self-assembly, carrier free nanoparticles, ferroptosis