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. (C) 2017 Elsevier Ltd. All rights reserved.