Functional Engineered Exosomes Loaded with Nanoenzymes Targeting the Proteasome and Inflammation for the Treatment of Rheumatoid Arthritis.

Mesenchymal stem cell -derived exosomes (MSCs-EXO) have been increasingly studied due to their high biosafety and excellent drug delivery properties. The use of MSCs-EXO as drug carriers for the treatment of rheumatoid arthritis (RA) has been reported. However, conventional exosomes cannot target the damaged area, significantly reducing their therapeutic efficacy. Therefore, this study proposes a strategy for the rational design of exosomes derived from genetically engineered mesenchymal stem cells, enabling them to target the inflammatory storm in the affected limb, regulate the immune microenvironment, and release similar to superoxide dismutase (SOD-like) and similar to catalase (CAT-like) nanoparticles to eliminate Reactive Oxygen and Nitrogen Species (RONS). RA provides a therapeutic platform for disease repair. MSC transduced with a lentivirus and carrying the anchoring peptide IL-4Rα secrete exosomes containing this peptide (IL-4.EXO), which demonstrates excellent targeting ability. These exosomes encapsulate Prussian blue nanoparticles (PB@IL-4.EXO), forming a synergistic composite exosome delivery system targeting inflammation sites, antioxidant stress, and promoting cartilage joint repair. Micro-CT shows a reduction in cartilage damage. Proteomics confirmed that it inhibits inflammation by affecting the proteasomal pathway through suppression of the PSMD4 protein. This exosome combines regulation of inflammation and antioxidant stress, offering a new therapeutic strategy for RA.