The effect of strong metal-support interaction (SMSI) has never been systematically studied in the field of nanozyme-based catalysis before. Herein, by coupling two different Pd crystal facets with MnO 2 , i.e., (100) by Pd cube (Pd c ) and (111) by Pd icosahedron (Pd i ), we observed the reconstruction of Pd atomic structure within the Pd-MnO 2 interface, with the reconstructed Pd c (100) facet more disordered than Pd i (111), verifying the existence of SMSI in such coupled system. The rearranged Pd atoms in the interface resulted in enhanced uricase-like catalytic activity, with Pd c @MnO 2 demonstrating the best catalytic performance. Theoretical calculations suggested that a more disordered Pd interface led to stronger interactions with intermediates during the uricolytic process. In vitro cell experiments and in vivo therapy results demonstrated excellent biocompatibility, therapeutic effect, and biosafety for their potential hyperuricemia treatment. Our work provides a brand-new perspective for the design of highly efficient uricase-mimic catalysts.