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Accurate cellular-recognition based disease therapy is of significance for precision medicine. However, except of specific antibody-coupling strategy, very few probes have been reported to efficiently discriminate normal cells and lesion cells through cellular microenvironment. Herein, we proposed a glucose selectively-lightened upconversion nanoprobe to recognize cancer cells from a pile of normal cells based on Warburg effect, that indicated a heightened demand for glucose intake for cancer cells. The nanoprobes were constructed by mesoporous silica-coated upconversion nanoparticles (UCNP@mSiO 2) with the crucial incorporation of a glucose-responsive modality, benzoboric acid (BA)-modified fluorescein molecules (FITC-BA). In cancer cells, the presence of elevated glucose concentrations triggered the transformation of FITC-BA to FITC-Glucose to recover nanoprobes' luminescence, however, the nanoprobes exhibited a shielded luminescent effect in healthy cells. To validate the hypothesis of accurate cellular-discrimination, a photodynamic therapy modality, riboflavin, with a specific ratio were also loaded into above UCNP@mSiO 2 nanoprobes for effective production of reactive oxygen species to kill cells. It was found that 97.8% of cancer cells were cleaned up, but normal cells retained a nearly 100% viability after 10 min laser illumination. By leveraging the metabolic disparity from Warburg effect, the nanoprobes offer a highly accurate cellular discrimination, and significantly mitigate "off-target" damage commonly associated with conventional therapies. A glucose selectively-lightened upconversion nanoprobe was designed to discriminate cancer cells from a pile of normal cells based on Warburg effect. [Display omitted] • The nanoprobes were constructed by mesoporous silica-coated upconversion nanoparticles with incorporation of a glucose-responsive modality, FITC-BA. • In cancer cells, the elevated glucose concentrations triggered the recovery of nanoprobes' luminescence, however, it exhibited a shielded luminescence in healthy cells. • After discrimination, 97.8% of cancer cells were cleaned up, but normal cells retained a nearly 100% viability by 10 min laser illumination. [ABSTRACT FROM AUTHOR]