Aerobic glycolysis fuels tumor proliferation, making it a critical target for tumor metabolic therapy. However, existing small-molecule inhibitors suffer from limitations like insufficient selectivity and systemic toxicity. In this study, a GSH-responsive molecularly imprinted polymer nanodelivery system (ML@MIP) was prepared for the precise delivery of the antimetabolite drug lonidamine (LND) and its synergistic treatment with CDT. ML@MIP employed LND-loaded metal-organic framework MOF-199 as the carrier and utilized the epitope of glucose transporter 1 (GLUT1) overexpressed on tumor cell membranes as the template. Through radical polymerization, an imprinted layer was constructed with specific recognition capabilities. Within the imprinted layer, GSH-sensitive disulfide bonds were introduced as crosslinking structural units into the imprinting network, endowing the material with controlled release properties triggered by the tumor microenvironment. ML@MIP actively recognized tumor cells with high GLUT1 expression. Upon entering the cell, high level GSH triggered disulfide bond cleavage in the imprinted layer and disassembly of the inner MOF-199 framework, enabling programmed drug release. The released LND inhibited hexokinase 2 (HK2) activity, which obstructed glycolysis pathways and further disrupted mitochondrial function. Concurrently, released Cu2+ was reduced by GSH to Cu+, which catalyzed the conversion of endogenous H2O2 into highly toxic hydroxyl radicals (·OH) through a Fenton-like reaction, thereby causing cellular damage. ML@MIP achieved high LND loading (78.2%) and a responsive release (66.6%). In vitro and in vivo experiments demonstrated that ML@MIP exhibited effective tumor targeting, significant antiproliferative effects, and good biocompatibility. This nanomaterial provides a novel, highly efficient nano-targeted delivery platform for precision synergistic cancer therapy.