NIR-enhanced Pt single atom/g-C_(3)N_(4)nanozymes as SOD/CAT mimics to rescue ATP energy crisis by regulating oxidative phosphorylation pathway for delaying osteoarthritis progression

Osteoarthritis(OA)progresses due to the excessive generation of reactive oxygen and nitrogen species(ROS/RNS)and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria.Highly active single-atom nanozymes(SAzymes)can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases.In this study,we innovatively utilised ligand-mediated strategies to chelate Pt^(4+)with modified g-C_(3)N_(4)byπ-πinteraction to prepare g-C_(3)N_(4)-loaded Pt single-atom(Pt SA/C_(3)N_(4))nanozymes that serve as superoxide dismutase(SOD)/catalase(CAT)mimics to scavenge ROS/RNS and regulate mitochondrial ATP production,ultimately delaying the progression of OA.Pt SA/C_(3)N_(4)exhibited a high loading of Pt single atoms(2.45 wt%),with an excellent photothermal conversion efficiency(54.71%),resulting in tunable catalytic activities under near-infrared light(NIR)irradiation.Interestingly,the Pt-N_(6) active centres in Pt SA/C_(3)N_(4)formed electron capture sites for electron holes,in which g-C_(3)N_(4)regulated the d-band centre of Pt,and the N-rich sites transferred electrons to Pt,leading to the enhanced adsorption of free radicals and thus higher SOD-and CAT-like activities compared with pure g-C_(3)N_(4)and g-C_(3)N_(4)-loaded Pt nanoparticles(Pt NPs/C_(3)N_(4)).Based on the use of H_(2)O_(2)-induced chondrocytes to simulate ROS-injured cartilage in vitro and an OA joint model in vivo,the results showed that Pt SA/C_(3)N_(4)could reduce oxidative stress-induced damage,protect mitochondrial function,inhibit inflammation progression,and rebuild the OA microenvironment,thereby delaying the progression of OA.In particular,under NIR light irradiation,Pt SA/C_(3)N_(4)could help reverse the oxidative stress-induced joint cartilage damage,bringing it closer to the state of the normal cartilage.Mechanistically,Pt SA/C_(3)N_(4)regulated the expression of mitochondrial respiratory chain complexes,mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase,to reduce ROS/RNS and promote ATP production.This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.