Biologically derived pharmaceuticals are increasingly useful therapeutics because their complexity and specificity make them effective and selective drugs. This same complexity, however, can render the biologics unstable and highly sensitive to environmental stressors. There are a variety of approaches to stabilizing proteins ranging from small molecule additives such as sugars or salts and covalent conjugation of polymers. Polymers offer suitably versatile scaffolds for biologics as they can be functionalized with stabilizing groups – in particular the sugar trehalose and a zwitterionic group, carboxybetaine. Chapter One provides an overview of the different trehalose based polymers that have been synthesized with a focus on those bearing trehalose as a pendent side chain. The different synthetic strategies are detailed along with a discussion of the advantages, limitations, and challenges of each. This is followed by a description of the various applications the polymers have been employed for including trehalose polymers as excipients for and conjugates of biologics.Chapter Two details the mechanism by which poly(trehalose methacrylate) stabilizes insulin against environmental stresses as well as the safety of the polymer. The polymer was found to inhibit both aggregation and degradation through deamidation with insulin exposed to heat without shifting insulin from the less stable monomer and dimer states to the more stable hexamer. Over 46 weeks at 4 �C, while the percent of intact insulin alone dropped significantly, the trehalose polymer maintained the majority of the insulin intact. The adaptive and innate mouse immune response to the polymer are explored with immunogenicity assays alone and in the presence of an immunogenic protein ovalbumin. To better understand the polymer’s safety and, in particular, the biodistribution and excretion, the synthesis of the trehalose methacrylate monomer and polymer was modified to incorporate the copper chelating tetraaza macrocycle DOTA for �PET and �CT imaging. It was found that the majority of the polymer was excreted in 24 h, with only residual amounts present at the final time point, 5 days post-injection. Chapter Three continues the exploration of poly(trehalose methacrylate) as an excipient for insulin but with a focus on fluid characterization and optimizing the formulation as a function of polymer molecular weight and molecular equivalents relative to insulin. A library of trehalose polymers with molecular weights ranging from 2.4 kDa to 29.3 kDa were readily synthesized, and, interestingly, up to 100 mg/mL these polymers displayed Newtonian fluid behavior and low viscosities, unlike many macromolecules. The formulation was optimized by mixing insulin with increasing relative concentrations of each polymer molecular weight, exposing the formulation to both heating and agitation stress, and then measuring the amount of intact insulin remaining. Of the best performing molecular weights and concentrations, the viscosities of the lowest weight per volume formulations were found to be above that of insulin alone, but manageable and tolerable. Chapter Four parallels the prior chapter by applying the same polymer, poly(trehalose methacrylate), as an excipient for the antibody Herceptin (generic name trastuzumab). Antibodies are another important class of biologics, and antibody formulations are known to have issues with high viscosities in addition to the instability against environmental stresses common to all biologics. In this chapter, the viscosity of the antibody alone, in market formulation, and formulated with the trehalose glycopolymer at high concentrations was measured. Additionally, the three formulations were evaluated for stabilization against mild heat stress. Chapter Five describes the synthesis of a zwitterionic, degradable polymer, poly(caprolactone-zwitterion), with a reactive endgroup. The polymer was designed to be conjugated with an alkyne containing protein, incorporated by an alkyne linker or non-canonical amino acid, for a degradable protein-polymer conjugate that could safely improve the half-life of the protein. The polymer was studied alone for adaptive immune response. Copper-catalyzed alkyne-azide click chemistry was used to install the polymer onto a growth hormone receptor antagonist (B2036) that had previously had a propargyl tyrosine installed at site of tyrosine 35. The bioactivity and pharmacokinetics of the site-selective protein-polymer conjugate were explored. Challenges towards synthesizing both polymers and conjugates are discussed.