A multifunctional supramolecular hydrogel that rapidly binds TNF-α for efficient reduction of synovial inflammation and cartilage destruction in rheumatoid arthritis

TNF-α is a key inflammatory cytokine in the progression of rheumatoid arthritis (RA), which is the most common inflammatory joint disorder and is characterized by persistent synovitis and cartilage destruction. However, systematic use of TNF-α inhibitors may cause undesirable side effects and fail to repair damaged cartilage. Here we design a self-assembling Nap-DFDFDEGPIRRSDS (termed FP) peptide that can form injectable supramolecular hydrogels and inhibit TNF-α within 15 min. Following integration of metformin-loaded hollow copper sulfide (CuS/MET, termed CM) nanoparticles (NPs) into these FPCM hydrogels, invasion by RA synovial fibroblasts and polarization of pro-inflammatory M1 type macrophages is reduced by inhibiting TNF-α and releasing MET. In addition, CuS NPs are chondroinductive, allowing the hydrogels to provide a suitable microenvironment for cartilage regeneration. More importantly, intraarticular injection of FPCM hydrogels significantly alleviates synovial inflammation and promotes cartilage repair in an adjuvant-induced arthritis mouse model. The therapeutic mechanism was shown to involve inhibition of the PI3K/AKT signaling pathway. Our approach synergistically inhibits inflammation and promotes tissue repair, thus holding promise for treatment of many kinds of inflammatory arthritis where TNF-α is overexpressed.