Therapeutic biomolecules often require frequent administration and supramolecular dosing to achieve therapeutic efficiencies and direct infusion into treatment or defect sites results in inadequate physiological response and at times severe side effects or mis-targeting. Delivery systems serve several purposes such as increased circulatory time, increased biomolecule half-life, and incorporation of new innovations can enable highly specific cell targeting and improved cell and nucleus permeability. Poly(lactic acid) (PLA) has become a “material of choice” due to wide availability, reproducible synthetic route, customization, versatility, biodegradability and biocompatibility. Furthermore, PLA is amenable to a variety of fabrication methodologies and chemistries allowing an expansive library correlating physio-chemical properties, characteristics, and applications. This article discusses challenges to biomolecule delivery, and classical approaches of PLA based biomolecule delivery and targeting strategies under development and in trials.