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The intrinsically fragile nature and leakage of the enzymes is a major obstacle for the commercial sensor of a continuous glucose monitoring system. Herein, a dual confinement effect is developed in a three dimensional (3D) nanocage-based zeolite imidazole framework (NC-ZIF), during which the high-loading enzymes can be well encapsulated with unusual bioactivity and stability. The shell of NC-ZIF sets the first confinement to prevent enzymes leakage, and the interior nanocage of NC-ZIF provides second confinement to immobilize enzymes and offers a spacious environment to maintain their conformational freedom. Moreover, the mesoporosity of the formed NC-ZIF can be precisely controlled, which can effectively enhance the mass transport. The resulted GOx/Hemin@NC-ZIF multi-enzymes system could not only realize rapid detection of glucose by colorimetric and electrochemical sensors with high catalytic cascade activity (with an 8.3-fold and 16-fold enhancements in comparison with free enzymes in solution, respectively), but also exhibit long-term stability, excellent selectivity and reusability. More importantly, the based wearable sweatband sensor measurement results showed a high correlation (>0.84, P < 0.001) with the levels measured by commercial glucometer. The reported dual confinement strategy opens up a window to immobilize enzymes with enhanced catalytic efficiency and stability for clinical-grade noninvasive continuous glucose sensor. [Display omitted] • A dual-confinement strategy that can doubly confine high-loading enzymes within NC-ZIF with unusual bioactivity and stability. • The mesoporosity of NC-ZIF can be precisely regulated to optimize the performance of packaged enzymes by adjusting the etching times. • The optimized GOx/Hemin@NC-ZIF catalyst could realize high sensitivity detection of glucose by colorimetric and electrochemical sensors. • The based wearable sweatband sensor measurement results show a high correlation (>0.84, P < 0.001) with the levels measured by commercial glucometer. [ABSTRACT FROM AUTHOR]