The oral route of drug administration is most preferred due to its ease of use, low cost,and high patient compliance.However, up to 40% drug on market and 70-90% active pharmaceutical ingredients (API)in R&D pipeline are poorly absorbable due to variousabsorptionbarriers, including low water solubility, chernicalinstability and enzymatic degradation, limited mucosal diffusion, and poor intestinal epithelialpermeability.The use of rationally designed and optimized drug delivery system to improve oral drug absorption from gastrointestinal (GI) tract is of great significance to the development of new drug formations for clinical use andtheefficieney of drug research.In our study, we found thatsupersaturated polymeric micelles (Super-PMs) prodigiously enhanced the oral absorption of cyclosporine A (CsA), and a moderately supersaturated Super-PMsis valuable alternative to high supersaturated formulations.In another study, we designed a class of core-shell corona nanoparticles (CSC) with improved mucus penetrationto improve oralabsorption of insulin.The core-shell nanocarriers were developed by enveloping chitosan nanoparticles (NC) into lipid vesicles (lipoparticles) or polymer-modified lipid vesicles (F-lipoparticles).Lipoparticles and F-lipoparticles exhibited significantly more efficient mucus penetration than NC.Consequently, higher cellular uptake of the nanocarfiers with E12 cells was observed.F-lipoparticles were associated with a 36 folds increase over free insulin and a 10 folds increase over NC, whereas, lipoparticles were associated with nearly 13 and 4 folds increases.In the pharmacological studies in diabetic rats,the orally administrated F-lipoparticles exhibited a better hypoglycemic effect with 2.52 folds higher relative bioavailability compared with non-coated NC.To improve drug epitheliumpermeability of itraconazole, an active transport delivery system,ligand wheat germ agglutinin (WGA) grafted nanocrystals were designed (WGA-cage-NCs).The cellular study showed that large amount of WGA-cage-NCs were adhered to Caco-2 cell membrane, and invaded into cells, resulting in a higher drug uptake than that of ordinary NCs (ONCs).After oral administration to rats,WGA-cage-NC were largely accumulated on the apical side of epithelium cells,facilitating drug diffusing across epithelium barrier.Interestingly, WGA-cage-NCs were capable of invading rat intestinal villi and reaching to lamina propria by transcytosis across goblet cells.The WGA-cage-NCs showed a significantly improved oral bioavailability, which was 17.5-and 2.41-folds higher than that of coarse crystals and ONCs, respectively.In conclusion, oral absorptionberries are multiple, the correspondingstrategies should be adopted to achieve optimal drug absorption.The knowledge gained in these studies will be highly critical and serves as good basis for future research in rational designofnanocarriers to improve oral drug delivery.