Polymers that are acid sensitive are very important for immunotherapy and cancer treatment. The lower pH present in the lysosome of a macrophage, or of a tumor cell can be targeted by the selective degradation of the pH sensitive polymer leading to the release of an encapsulated drug inside the targeted cell. Towards this goal, a library of polyurethanes with different hydrophobicities containing the same acid-degradable dimethyl ketal moiety embedded in the polymer main chain have been prepared. The polymers were designed to hydrolyze at different rates in mildly acidic conditions as a function of their hydrophobicity to afford small molecules only with no polymeric byproduct. The library of polymers was screened for the formation of microparticles using a double emulsion technique. The microparticles that were obtained degraded significantly faster at acidic pH (5.0) than at physiological pH (7.4) with degradation kinetics related to the hydrophobicity of the starting polymer. In vitro studies demonstrated the ability of the FITC-BSA loaded microparticles to be phagocytosed by macrophages resulting in a 10-fold increase in the protein uptake compared to a free protein control; in addition, the microparticles were found to be nontoxic at the concentrations tested of up to 1 mg/mL. The particles generated drastically increased the ability of macrophages to present antigens to T-cells compared to nonencapsulated protein. Overall, these new class of polymers are easily tunable to deliver the protein in a pH sensitive manner and have the potential to increase the efficacy of protein vaccines.