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

Abstract

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-1β (IL-1β) 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.