activity (2007), [1] a wide range of nanomaterials (i.e., nanozymes) has been found to exhibit this property. [2][3][4][5] However, the mechanism behind those transition metal-based mimetics is not clear until recently. [6][7][8] As illustrated in Figure 1a, the redox between their surface M n+ (oxidation) and H 2 O 2 (reduction) first generates OH radicals (step (a)), which later oxidize substrates (e.g., tetramethylbenzidine (TMB)) giving a color change for the evaluation of activity (step (b)). To complete the catalytic cycle, OH radicals must oxidize other H 2 O 2 to produce HO 2 radicals (step (c)) for the regeneration of surface M n+ (step (d)). Since the later three steps are two orders of magnitude faster than step (a), the redox rate of surface M n+ with H 2 O 2 is thus the key step affecting the peroxidase-like activity of nanozymes. [6] Our recent study also suggests that the activity of a given nanozyme can be further enhanced by tuning the initial concentration of surface M n+ and its local structure for H 2 O 2 activation. [8] This mechanism is distinct from that of peroxidases. Taking horseradish peroxidase (HRP) as an example (Figure 1b), [9] its active site consists of a Fe(III)-protoporphyrin IX with His-42 and Arg-38 in the reaction pocket coactivating the OO bond of H 2 O 2 . The adsorbed H 2 O 2 first oxidizes Fe(III) (i.e., the resting state) to Fe(IV)-oxo with a radical retained on the porphyrin ring (the compound I). This reactive Single-atom catalysts have attracted attention in the past decade since they maximize the utilization of active sites and facilitate the understanding of product distribution in some catalytic reactions. Recently, this idea has been extended to single-atom nanozymes (SAzymes) for the mimicking of natural enzymes such as horseradish peroxidase (HRP) often used in bioanalytical applications. Herein, it is demonstrated that those SAzymes without constructing the reaction pocket of HRP still undergo the OH radical-mediated pathway like most of the reported nanozymes. Their positively charged single-atom centers resulting from support electronegative oxygen/nitrogen hinder the reductive conversion of H 2 O 2 to OH radicals and hence display low activity per site. In contrast, it is found that this step can be facilitated over their metallic counterparts on cluster nanozymes with much higher site activity and atom efficiency (cf. SAzymes with 100% atom utilization). Besides the mimicking of HRP in glucose detection, cluster nanozymes are also demonstrated as a better oxidase mimetic for glutathione detection.