A magnesium-based coordination container as a multi-drugs co-loaded system for boosting anti-inflammatory therapy in joints

Abstract As one of the most complicated joint structures, temporomandibular joint (TMJ) is susceptible to inflammatory reaction caused by osteoarthritis, rheumatoid arthritis and so on. The treatment for TMJ inflammation is still challenging due to the rapid clearance and lack of selectivity of traditional medication. Herein, we design a novel discrete sulfonylcalix[4]arene-based magnesium(II) coordination container, MgDHIA, which features satisfactory biocompatibility, appropriate molecular size and multiple binding domains. MgDHIA is capable of selectively encapsulating rapamycin (RAPA) in the endo cavity and folic acid (FA) in the exo cavities to form the co-loaded system RAPA-FA@MgDHIA, which exhibits outstanding activated macrophages targeting, stepwise releasing and cellular uptake behaviors. For therapeutic aspect, the RAPA-FA@MgDHIA reprograms the phenotype of polarized macrophages, specifically, transforming the pro-inflammatory M1 macrophages to anti-inflammatory M2 phenotype by inhibiting NF-kB pathway. The in vivo studies also demonstrate that the RAPA-FA@MgDHIA presents higher accumulation in inflamed synovial tissues, protecting the articular cartilage and subchondral bone structures by alleviating synovial inflammation. Anyway, we first evaluate the application of coordination container-based nanomedicine in treatment of inflammatory TMJ, demonstrating that the drug and targeting agents co-loaded coordination container remarkably boosts the therapeutic efficacy of traditional medication, thus providing a promising approach for anti-inflammatory treatment in joints.