An Injectable, Click‐Cross‐Linked Small Intestinal Submucosa Drug Depot for the Treatment of Rheumatoid Arthritis

Here, a click‐cross‐linked small intestine submucosa (SIS) drug depot is described for the treatment of rheumatoid arthritis (RA). To the best of the knowledge, there have been no studies related to the intra‐articular injection of methotrexate (Met)‐loaded click‐cross‐linkable SIS (Met‐loaded Cx‐SIS) for RA treatment. As the key objective of this work, injectable formulations of tetrazine‐modified SIS (TE‐SIS) and transcyclooctene‐modified SIS (TC‐SIS) are employed as drug depots. Within a few seconds, the simple mixing of equal amounts of TE‐SIS and TC‐SIS suspensions forms a gelatinous click‐cross‐linked SIS (Cx‐SIS) drug depot in vitro and in vivo. The formed Cx‐SIS depot is maintained in the articular joint over an extended period, while SIS alone rapidly disappears. Injectable formulations of Met‐loaded Cx‐SIS and Met‐loaded SIS are prepared and then injected into articular joints to form drug depots. Compared to animals treated with Met‐loaded SIS, RA animals treated with Met‐loaded Cx‐SIS show effective RA repair, as well as extensive regeneration of chondrocytes and glycosaminoglycan deposits. Collectively, these results indicate that the Met‐loaded Cx‐SIS depot is successfully formed after intra‐articular injection of click‐cross‐linkable SIS, and that this formulation induces long‐lasting Met release and allows Met to act effectively in the articular joint, resulting in RA repair.