Biologics increasingly are being used for the treatment of many diseases. These treatments typically require repeated doses administered by injection. Alternate routes of administration, particularly oral, are considered favorable because of improved convenience and compliance by patients, but physiological barriers such as extreme pH level, enzyme degradation, and poor intestinal epithelium permeability limit absorption. Encapsulating biologics in drug delivery systems such as polymeric nanoparticles prevents inactivation and degradation caused by low pH and enzymes of the gastrointestinal tract. However, transport across the intestinal epithelium remains the most critical barrier to overcome for efficient oral delivery. This review focuses on recent advances in polymeric nanoparticles being developed to overcome transport barriers and their potential for translation into clinical use.