<p>Native folded proteins rely on sculpting the local chemical environment of their active or binding sites, as well as their shapes, to achieve functionality. In particular, proteins use hydration frustration—control over the dehydration of hydrophilic residues and the hydration of hydrophobic residues—to amplify their chemical or binding activity. Here we uncover that single-polymer-chain nanoparticles formed by random heteropolymers comprising four or more components can display similar levels of hydration frustration. We categorize these nanoparticles into three types based on whether either hydrophobic or hydrophilic residues, or both types, display frustrated states. We propose a series of physicochemical rules that determine the state of these nanoparticles. We demonstrate the generality of these rules in atomistic and simplified Monte Carlo models of single-polymer-chain nanoparticles with different backbones and residues. Our work provides insights into the design of single-chain nanoparticles, an emerging polymer modality that achieves the ease and cost of fabrication of polymeric material with the functionality of biological proteins.</p><p></p>