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Patients with diabetes mellitus (DM) suffer from a high risk of fractures and poor bone healing ability. Surprisingly, no effective therapy is available to treat diabetic bone defect in clinic. Here, a 3D printed enzyme‐functionalized scaffold with multiple bioactivities including osteogenesis, angiogenesis, and anti‐inflammation in diabetic conditions is proposed. The as‐prepared multifunctional scaffold is constituted with alginate, glucose oxidase (GOx), and catalase‐assisted biomineralized calcium phosphate nanosheets (CaP@CAT NSs). The GOx inside scaffolds can alleviate the hyperglycemia environment by catalyzing glucose and oxygen into gluconic acid and hydrogen peroxide (H2O2). Both the generated H2O2 as well as the overproduced H2O2 in DM can be scavenged by CaP@CAT NSs, while the initiated hypoxic microenvironment stimulates neovascularization. Moreover, the incorporation of CaP@CAT NSs not only enhance the mechanical property of the scaffolds, but also facilitate bone regeneration by the degraded Ca2+ and PO43− ions. The remarkable in vitro and in vivo outcomes demonstrate that enzymes functionalized scaffolds can be an effective strategy for enhancing bone tissue regeneration in diabetic conditions, underpinning the potential of multifunctional scaffolds for diabetic bone regeneration. [ABSTRACT FROM AUTHOR]