In the application of delivery of therapeutics, nanostructures of various composition have been employed due to their capacity to act as a host for lipophilic payloads. Advances in the synthetic preparation, size, morphology, and chemical or physical characteristics of polymers have impacted their development and versatility. A detailed understanding of polymeric nanoparticle host-guest properties is crucial to their practical translation to specific delivery applications. Further, these features must be highly tailorable to overcome biological barriers, stably encapsulate their therapeutic contexts, and exhibit payload release selectively in the target environment. In this dissertation, we aim to rationally design polymeric nano-scale assemblies with well-defined compositions and unique stimuli-responsiveness to achieve desirable host properties and interfacial characteristics. While each chapter is specific in focus, we expect that the fundamental findings in this dissertation to broadly impact principles in drug delivery, including nanoparticle biodistribution (chapter 2), hydrophobic delivery (chapter 3), stimuli-responsive “smart” materials (chapter 4), and polymeric composition development (chapter 5).