We report a class of 17-amino-acid peptides that undergo a sharp hydrophobicity transition at pH around 7. Nanoparticles made of such peptides exhibit ultra pH-sensitivity and autonomous drug-eluting properties, which are beneficial for cancer drug delivery. At pH above 7, the peptides bind water-insoluble drug cargo and form a nanoparticle that protects its cargo from serum proteins. Sensing tumor’s mildly acidic pH (≤7.0), nanoparticle peptides undergo a hydrophobic-to-hydrophilic transition and release drug molecules in the interstitial fluid as the nanoparticle migrates down the pH gradient in the tumor. When this pH-sensing and drug-eluting nanoparticle formulation was used to deliver two drugs, lonidamine inhibiting tumor bioenergetics and bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) targeting cancer glutamine metabolism, to triple negative human breast cancer xenografts, the nanoparticle drug demonstrated superior efficiency compared to the respective standard formulation.