Tumor cells intensively engage in metabolic reprogramming for enhancing the availability of glycolytic metabolites and support cell proliferation. As the most important rate-limiting
enzyme in aerobic glycolysis, activating the
pyruvate kinase muscle
isoform 2 (PKM2) from dimers to tetramers has become a key
tumor chemotherapy method to control
glucose metabolism. Herein, we developed a
glycopeptide-based PKM2 nano-activator, which could induce the tetramerization of PKM2 based on
serine bonding to Domain C of PKM2. The bound and trapped PKM2 tetramers significantly hindered glycolytic intermediates, prevented the nucleus translocation of dimeric PKM2, and ultimately inhibited the proliferation, chemoresistance and
metastasis of
tumor. The
glycopeptide assembled into nanoparticles under aqueous conditions and in the circulation, which in situ transformed into PKM2 nano-activator with nanofibrillar structure after specifically activated by
O-GlcNAcase recognition upregulated in a wide range of human
tumors. Moreover, the
glycopeptide-based PKM2 nano-activator successfully accumulated at the
tumor sites and boosted the chemo-
drug sensitivity against prostate and breast
cancers. Attributed to these intriguing results, the newly developed
glycopeptide-based PKM2 nano-activator can be envisioned a promising candidate for the treatment of
tumors by switching catabolic pathways.