Metal-organic-framework nanoparticles (MOF NPs) have been increasingly used to encapsulate therapeutic enzymes for delivery. To better interface these MOF NPs with biological systems, researchers have coated them with natural cell membranes, enabling biomimicking properties suitable for innovative biomedical applications. Herein, we report that the enzymatic activity of cell-membrane-coated MOF NPs can be significantly enhanced by reducing membrane cholesterol content. We demonstrate such cholesterol-enzymatic activity correlation using zeolitic imidazolate framework-8 MOF NPs to encapsulate catalase, horseradish peroxidase, and organophosphate hydrolase, respectively. MOF NPs coated with membranes of human red blood cells or macrophages show similar outcomes, illustrating the broad applicability of this finding. The mechanistic investigation further reveals that reducing cholesterol levels effectively enhances membrane permeability likely responsible for the increased enzymatic activity. These results also imply a facile approach to tailoring the enzymatic activity of cell-membrane-coated MOF NPs by simply tuning the membrane cholesterol level.