Injectable Amphipathic Artesunate Prodrug-Hydrogel Microsphere as Gene/Drug Nano-Microplex for Rheumatoid Arthritis Therapy

Artemisinin and its derivatives (artemisinins) are first-line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid-acting medicines with an extremely short half-life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long-acting gene/artemisinin co-delivery nano-microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co-delivery nano-lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug-embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin-embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF-α siRNA/artemisinin co-delivery nano-microplex (MTAsi@MG) is further prepared by immobilization of TNF-α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano-microplex for intra-articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long-term treatment is first realized. Undoubtedly, this intra-articular injectable TNF-α siRNA/artemisinin co-delivery nano-microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co-delivery systems for RA therapy.