This review article explores the transepithelial transport of nanoparticles in oral drug delivery, focusing on the surface and holistic properties that influence this process. The authors highlight the complex transportation pathway, including cellular uptake, intracellular trafficking, and exocytosis by intestinal epithelial cells, which are crucial for nanoparticles to enter the bloodstream and exert therapeutic effects. Key factors such as surface properties (ligand modification, surface charge, hydrophilicity/hydrophobicity, intestinal protein corona formation) and holistic properties (particle size, shape, rigidity) are discussed in detail. The article emphasizes the importance of understanding these properties to enhance transepithelial transport efficiency and design effective oral drug delivery systems. It also outlines the parameters to be considered for the subsequent design of oral drug delivery systems, providing a comprehensive overview of the current research progress and future strategies.This review article explores the transepithelial transport of nanoparticles in oral drug delivery, focusing on the surface and holistic properties that influence this process. The authors highlight the complex transportation pathway, including cellular uptake, intracellular trafficking, and exocytosis by intestinal epithelial cells, which are crucial for nanoparticles to enter the bloodstream and exert therapeutic effects. Key factors such as surface properties (ligand modification, surface charge, hydrophilicity/hydrophobicity, intestinal protein corona formation) and holistic properties (particle size, shape, rigidity) are discussed in detail. The article emphasizes the importance of understanding these properties to enhance transepithelial transport efficiency and design effective oral drug delivery systems. It also outlines the parameters to be considered for the subsequent design of oral drug delivery systems, providing a comprehensive overview of the current research progress and future strategies.