(Bio)macromolecules ranging from proteins and carbohydrates to synthetic polymers and nanoparticles are critical components of many therapeutics, including vaccines. These materials can deliver molecular cargo, interact with receptors, and alter cellular processes on account of their physicochemical properties to modulate the immune response. Despite the promise of these materials, there are few studies probing how different physicochemical parameters (e.g., size, shape, charge, or valency) can generate divergent immune responses. As such, there are a limited number of chemical approaches which use these materials toward the design of new, more effective vaccines. This thesis explores several approaches toward the design, characterization, and implementation of (bio)macromolecules that engage the immune system in controlled manners to facilitate desired immunological responses in the context of vaccination. Libraries of cationic polymers and cellulose nanocrystals with different physicochemical properties are generated to understand how these materials engage the immune system. By mapping the physicochemical parameters that result in toxic, immunogenic, and biocompatible responses, better materials for drug and gene delivery, vaccine adjuvants, and antimicrobial coatings can be rationally designed. Additionally, small molecule vaccine adjuvants are formulated both as liposomes and as bioconjugate materials to control their biodistribution and enhance the innate and adaptive immune response. A class of small molecules, the Cyclin Dependent Kinase inhibitors, which target the NLRP3 inflammasome are identified and formulated to induce robust Th1-biased immune responses. Moreover, antigen-adjuvant bioconjugates comprised of Toll-like receptor 9 agonists are synthesized and shown to allow for dose sparing in the adaptive immune response toward a model antigen. Altogether, these works serve to grow the repertoire of macromolecular tools available toward vaccine design.