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Interactions between drug molecules, nanocarrier components, and surrounding media influence the properties and therapeutic efficacies of nanomedicines. In this study, we investigate the role that reversible covalent loading of a hydrophobic drug exerts on intra-nanoparticle physical properties and explore the utility of this payload control strategy for tuning the access of active agents and, thereby, the stimuli sensitivity of smart nanomaterials. Glutathione sensitivity was controlled via altering the degree of hydrophobic payload l