To enhance oral drug bioavailability, we propose mucoadhesive, nanostructured microparticles (PLGA/ PEG NM) as a drug-delivery vehicle. The PLGA/PEG NM herein retain nanofibrous structures within microparticles, and possess a seven-fold increase in specific surface area than conventional spherical microparticles, allowing for synergistic improvement of a mucoadhesive property. In vivo evaluations demonstrated that PLGA/PEG NM showed prolonged retention in the gastrointestinal tract, as compared to control microparticles. When PLGA/PEG NM was loaded with losartan, an oral anti-hypertension drug, drug’s bioavailability increased by two-fold in comparison to a bolus losartan solution. Therefore, the PLGA/PEG NM are a promising carrier for oral drug delivery.