Hydrogels have proven to be useful materials for myriad biomedical applications, with the hydrated network often serving as a crude synthetic extracellular matrix capable of interfacing with tissues in the body. Supramolecular crosslinking of these networks allows for incorporation of tunable dynamics within the network backbone, better mimicking the dynamic properties of natural tissues. Specific and tunable interactions at network crosslinks can be achieved by supramolecular host-guest complexation. In this work, I have chosen to focus on the host macrocycle cucurbit[7]uril (CB[7]) due to the wide range and exceedingly high upper limits of its attainable binding affinities in monovalent binding to small molecule motifs. Herein, I first survey commonly available host-guest systems and review design considerations of tuning the complimentary interactions underlying this supramolecular paradigm. I then demonstrate the incorporation of CB[7] at the crosslinks of hydrogel networks, and subsequent tuning of crosslink host-guest binding affinity, propagates across length scales to allow for control of resultant bulk material properties. Next, I investigate the impact of crosslink affinity and dynamics on diffusion of macromolecular solutes within a hydrogel network, incorporating discussions on the interplay between mean mesh size, model drug molecular weights, thermodynamics of crosslink reorganization, optimization of ideal networks, and deviations from classical Stokes-Einstein predictions. This work transitions to a critical evaluation of the disconnect between in vitro and in vivo modeling of drug delivery by hydrogel encapsulation. My final investigation of fundamental phenomena focuses on effects of bulk material properties arising from differences in guest orientation within crosslinks, leveraging asymmetric guest topology to underscore a key aspect of host-guest system design considerations previously unaddressed. Transitioning to applications of such fundamental phenomena, I next discuss my contributions to the use of CB[7]-based biomaterials in the targeted delivery of chemotherapeutics. Through the pre-targeting of a site of interest in vivo with a CB[7]-rich hydrogel, delivery of guest-modified chemotherapeutic drugs were directed to and sequestered at the site of interest as a function of supramolecular host-guest affinity. This drug delivery platform parallels modern advances in antibody-drug conjugates (ADCs) but achieves a remarkable improvement in drug delivery efficiency while reducing off-target effects. Lastly, I introduce the selective binding of fentanyl by CB[7] and present a novel synthesis for a modified CB[7] designed for decorating nanoparticles, making this selective binding amenable to quantification via surface enhanced Raman spectroscopy (SERS), in response to the current opioid epidemic national emergency.