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An artificial "closed‐loop" system that mimics the glucose‐responsive insulin secretion of pancreas β‐cells can potentially improve the treatment efficacy for diabetes. Herein, a lipid bilayer‐coated polymeric nanoparticle (NP) with "core–shell" structure is designed. As far as it is known, it is the first and only intravenous nanoplatform utilizing enzymatic‐oxidation scheme to achieve glucose‐responsive insulin delivery so far. Ethoxy acetal–derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" loaded with insulin, and coloading glucose oxidase (GOx) and catalase (CAT) endow the "inner core" excellent glucose‐sensitive ability. Red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell." It collectively provides a closed microenvironment for GOx‐based enzymatic‐oxidation scheme and camouflages it from elimination. Above all, the anchored glucose transporters (GLUTs) on the "outer shell" are able to sense blood glucose levels and facilitate the transport of outer blood glucose getting inside. Under a hyperglycemic condition, the internalized glucose is catalytically converted into gluconic acid with the aid of the GOx and subsequently triggers acid degradation of the "inner core" to secrete insulin. By governing the blood glucose levels on an automatic and continuous basis, the RBCm‐Ace‐DEX NPs can effectively respond to hyperglycemia and turn to resting conditions under normoglycemia. Ethoxy acetal derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" and red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell". This glucose‐responsive nanoplatform can steadily circulate in the blood at normalglycemia. While under hyperglycemic condition, the glucose internalized by the anchored GLUTs is catalytically converted into gluconic acid with the aid of GOx and CAT and subsequently triggers acid degradation of RBCm‐Ace‐DEX NPs to secrete insulin. [ABSTRACT FROM AUTHOR]