Here we present a "smart" xenon-129 NMR biosensor that undergoes a peptide conformational Change and labels cells in acidic environments. To a cryptophane host molecule with high Xe affinity, we conjugated a 30mer EALA-repeat peptide that is a-helical at pH 5.5 and disordered at pH 7.5. The Xe-129 NMR chemical shift at room temperature was strongly pH-dependent (Delta delta = 3.4 ppm): delta = 64.2 ppm at pH 7.5 vs delta = 67.6 ppm at pH 5.5, where Trp(peptide)-cryptophane interactions were evidenced by Trp fluorescence quenching. Using hyper-CEST NMR, we probed peptidociyptophane detection limits at low-picomolar (10(-11) M) concentration, which compares favorably to other NMR pH reporters at 10(-2)-10(-3) M. Finally, in biosensor-HeLa cell solutions, peptide-cell membrane insertion at pH 5.5 generated a 13.4 ppm downfield cryptophane-Xe-129 NMR chemical shift relative to pH 7.5 studies, This highlights new uses for Xe-129 as an ultrasensitive probe of peptide structure and function, along with potential applications for pH dependent cell labeling in cancer diagnosis and treatment.