Prodrug-loaded micelles targeting articular cavity reactive oxygen species for rheumatoid arthritis treatment

Oxidative stress plays an important role in the pathogenesis of rheumatoid arthritis (RA). Excessive reactive oxygen species (ROS) activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, release multiple inflammatory mediators, stimulate macrophage polarization, and exacerbate the inflammatory response. In response to the pathological features of RA, we designed a dihydroartemisinin (DHA)-ROS sensitive prodrug loaded into carriers of Soluplus and Vitamin E polyethylene glycol succinate (TPGS) using a thin film hydration to expect that the nano-micelles could target for delivery to the inflammation site due to extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effects, and the higher ROS level in articular cavity resulting in the breaking of ROS sensitive bonds and the release of anti-inflammatory DHA and antioxidant cinnamaldehyde (CA), avoiding the instability of DHA and CA circulating in the body. In addition, prodrug-carrying nanomicelles (DHA∼CA@NM) promoted the polarization of M1 to M2 macrophages, which exerted a series of anti-inflammatory effects. Intravenously injected DHA∼CA@NM could accumulate at inflamed joints of CIA rats, attenuate joint damage and bone erosion, and inhibit synovial hyperplasia and formation of pannus, thus alleviating joint inflammation and displaying high biosafety. The protective mechanism of DHA∼CA@NM may be related to the inhibition of NLRP3 inflammasome, which has the potential to be developed as a safe and effective nano-formulation for the treatment of RA.