Engineering non-covalently assembled protein nanoparticles for long-acting gouty arthritis therapy.

As an incurable metabolic disease, gouty arthritis (GA) requires long-term treatment with frequent drug administration several times per day. Compared to non-specific small organic medications, interleukin-1ß (IL-1ß) blocking therapies, such as IL-1 receptor antagonist (IL-1Ra), show great therapeutic potential in clinical trials of GA. However, IL-1Ra application is starkly limited due to its short half-life and poor bioavailability. Herein, we demonstrate a new type of nanotherapeutic formulation via noncovalent assembly of an engineered IL-1Ra chimera protein. PEGylation was employed to induce such assembly by exploiting electrostatic complexation and hydrophobic interactions. The engineered protein nanoparticles had a combination of biocompatibility, improved bioavailability and therapeutic performance. It showed extraordinary long-term anti-inflammatory effect and robust bio-efficacy for GA therapy in acute GA rat models. Strikingly, this nanoprotein system possesses an ultralong half-life of 27 hours and a bioavailability 7 times higher than that of pristine IL-1Ra, thus extending the dosing interval from several hours to more than 3 days. Therefore, our noncovalent assembly strategy via an engineered chimeric protein empowers the construction of potent delivery nanosystems for efficient GA treatment, and this might be adapted for other therapeutics to form long-acting formulations.

Magnetic Targeting of HU-MSCs in the Treatment of Glucocorticoid-Associated Osteonecrosis of the Femoral Head Through Akt/Bcl2/Bad/Caspase-3 Pathway.

PURPOSE: Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that eventually develops into a joint collapse and results in joint dysfunction. Early intervention and treatment are essential for preserving the joints and avoiding hip replacement. In this study, a system of human umbilical mesenchymal stem cells-supermagnetic iron oxide nanoparticles (NPs) @polydopamine (SCIOPs) was constructed. The magnetic targeting system gathers in the lesion area, inhibits the apoptosis of bone cells, enhances osteogenic effect, and effectively treats ONFH under external magnetic field. MATERIALS AND METHODS: The supermagnetic iron oxide NPs @polydopamine (SPION@PDA NPs) were characterized by transmission electron microscopy and zeta potential, respectively. The effects of SPION@PDA NPs on the viability, proliferation, and differentiation of stem cells were detected by the CCK8 method, flow cytometry, and staining, respectively. The serum inflammatory indicators were detected by Luminex method. The bone mass of the femoral head was analyzed by micro computed tomography. The expression of apoptosis and osteoblast-related cytokines was detected by Western blotting. The osteogenesis of the femoral head was detected by histological and immunohistochemical sections. RESULTS: The SCIOPs decreased the pro-inflammatory factors, and the micro CT showed that the bone repair of the femoral head was enhanced after treatment. The hematoxylin and eosin sections also showed an increase in the osteogenesis in the femoral head. Western blotting results showed and increased expression of anti-apoptotic proteins Akt and Bcl-2, decreased expression of apoptotic proteins caspase-3 and Bad, and increased expression of osteogenic proteins Runx-2 and Osterix in the femoral head. CONCLUSION: Under the effect of magnetic field and homing ability of stem cells, SCIOPs inhibited the apoptosis of osteoblasts, improved the proliferation ability of osteoblasts, and promoted bone repair in the femoral head through the Akt/Bcl-2/Bad/caspase-3 signaling pathway, thereby optimizing the tissue repair ability.