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 loading of disulfide-linked camptothecin-conjugated sugar-based nanomaterials. Increases in degrees of camptothecin conjugation (fCPT) decreased aqueous accessibility and reduced glutathione-triggered release. Although the lowest fCPT gave the fastest camptothecin release, it resulted in the lowest camptothecin concentration. Remarkably, the highest fCPT resulted in a 5.5-fold improved selectivity against cancer vs noncancerous cells. This work represents an advancement in drug carrier design by demonstrating the importance of controlling the amount of drug loading on the overall payload and its availability.