Table 1.

The influence of nanomaterial characteristics on cellular uptake and internalization pathways and strategies for enhancing their uptake

Characteristic		Cellular uptake	Internalization pathway	Strategy
Size	<10 nm	Renal clearance	–	Add a penetration enhancer (PPS, polyacrylate, chitosan, phytic acid, self-assembling lipid-like peptides, thiomers, and lectins) to macromolecules to open TJs
	10–10 nm	Peyer’s patches	<50 nm: clathrin and caveolae independent; 50–100 nm: caveolae dependent
100–200 nm	Removed by MPS	120 nm: clathrin dependent
200–300 nm	Spleen	Macropinocytosis
Surface composition	Hydrophobic	Immune cells	N/A	Avoid phagocytic clearance, prolong drug circulation, and improve biocompatibility by (i) adding hydrophilic polymers (PEGylation); or (ii) having biomimetic surfaces (CD47, leukocytes)
Charge	Positive	Highly positive: taken up by macrophages	Clathrin and macropinocytosis	Positively charged nanomaterials interact more strongly with negatively charged intestinal cell membrane
	Neutral	Appropriate for long circulation residency	N/A
Negative	Highly negative: taken up by macrophages; slightly negative: appropriate for long circulation residency	Caveolae mediated
Shape	Spherical	Macrophages	N/A	Elliptical particles that escape macrophages and, after exposure to stimuli, change to a spherical form for better internalization
Asymmetrical	N/A	N/A
Elasticity and solubility	Soft	Avoid immune system	Macropinocytosis	Add fatty acids and/or substitute amino acids
	Hard	N/A	Clathrin-dependent mechanisms