Table 3.

Summary of the main pathways that nanoparticles can take to cross the intestinal epithelium (Yu et al., 2016; Reinholz et al., 2018).

Paracellular	Transport through the intercellular space between intestinal epithelial cells (enterocytes)
	Intercellular spaces have an aqueous environment and rely on passive transport
	Limitations
	Passage of nanoparticles is restricted by the narrow tight junction space (0.3 to 20 nm)
	Potential for toxicity with the passage of other gastrointestinal content in the chyme
Transcellular	Transport through epithelial cells (enterocytes) by transcytosis, which includes endocytosis, intracellular trafficking, and exocytosis
	Enterocytes represent 90–95% of the cells lining the GI tract
	Nanoparticles can potentially undergo indirect transport to the systemic circulation via the hepatic portal system or direct transport to the systemic circulation via the intestinal lymphatic system
	Limitations
	Internalized nanoparticles are usually transported to lysosomes that contain a variety of enzymes for degradation
	Enterocytes have enzymes in the microvilli of the brush border membrane and within the glycocalyx
	Mucus layer and glycocalyx of enterocytes are thicker compared to M cells
M-cell-mediated	Transport through M cells (microfold cells) by transcytosis, which includes endocytosis, intracellular trafficking, and exocytosis
	M cells are mainly localized in Peyer's patches in the small intestine and have reduced intracellular enzymatic activity
	Mucus layer and glycocalyx of M cells are considerably thinner compared to enterocytes, allowing easier access
	Nanoparticles can potentially be captured by macrophages and dendritic cells in the Peyer's patches (beneficial for the development of oral vaccinations) or undergo passive lymphatic targeting followed by systemic drug delivery
	Limitations
	Absorption of nanoparticles is restricted due to the low proportion of M cells (~1%) in the intestinal epithelium
	Cellular uptake can be low due to a lack of specificity of nanoparticles towards M cells