A D‐Y Shaped Neuropeptide Y Mimetic Peptide‐Dye Self‐Assembly with Maximal Emission Beyond 1300 nm and Glioma Mitochondrial Activity Modulation

Abstract Neuropeptide Y (NPY), as one of the most abundant neuropeptides known, is widely distributed in the central and peripheral nervous system. However, most of the reported NPY‐mimetic peptides are hard to cross the blood–brain barrier, target glioma mitochondria, and achieve self‐assembly nanostructure in situ. Here, based on the α‐helix structure of the novel chiral NPY‐mimetic peptides ^D/LNPY(14), a Y‐shaped peptide is designed with the sequences that can be recognized by enterokinase and achieved nanofibers conversion in glioma cell mitochondria. Coupling the Y‐shaped NPY‐mimetic peptide with the NIR‐II fluorophore IR1048, a red‐shifting of the fluorescence spectrum beyond 1300 nm is achieved through self‐assembly. After the self‐assembly in glioma mitochondria, the formed nanofibers can promote intracellular mitochondrial ROS production and extend the NIR‐II fluorescence imaging time to at least 7 days in vivo. This work for the first time endows the self‐assembly of α‐helical‐based chiral NPY‐mimetic peptides, providing a novel strategy for glioma subcellular regulation enhanced antitumor treatment guided by NIR‐II fluorescence imaging.