The nanozymes of protein nanotubes-constructed microspheres with dual peroxidase- and catalase-like properties for M1-to-M2 macrophages repolarization and the synergistic anti-rheumatoid arthritis effect with loaded capsaicin

Rheumatoid arthritis (RA) is an inflammatory disease driven by M1 macrophages via release of abundant inflammatory cytokines. Eliminating M1 macrophages or inducing their transformation into anti-inflammatory M2 macrophages is one of the key mechanisms to reduce inflammation. Here, we report protein nanotubes cross-linked microspheres (NTMs), which exhibit nanozyme-like properties. The NTMs can alleviate RA via repolarizing inflammatory macrophages from M1 to M2, and modulating the articular redox homeostasis. Redox metal-centered NTMs possess both peroxidase- and catalase-like activities, allowing them to eliminate endogenously over-expressed ROS and collaboratively generate dissolved oxygen. NTMs is biologically safe, and can be phagocytosed by macrophages and subsequent presence within the cytoplasm. In vitro, NTMs showed anti-inflammatory effects by promoting the transition of M1 macrophages towards the anti-inflammatory M2 phenotype. Most importantly, in vivo, adjuvant-induced arthritis administrated with capsaicin-loaded NTMs showed an improved cartilage structure and organized nuclei structure, which are close to healthy native cartilage. These findings demonstrate that NTMs can modulate the microenvironment of joint via the redox enzyme-mimetic strategy, and capsaicin also showed a synergistic anti-inflammatory and pain-relief effect, which in total possessed a high potential for anti-RA treatments.