Table 2.

Barriers to the transport of siRNAs and miRNAs to target cells

Level	Barriers
Circulation	Non-specific interactions with serum proteins, resulting in nanocarrier degradation, dissociation, or aggregation. Clearance by the renal system for particles less than 6–10 nm in size. Nanocarrier toxicity and immune response can be induced.
Tissue permeability	Endothelium penetration. Transport from the bloodstream to a desired tissue.
Extracellular	Extracellular stability and diffusion. Differences in the pH, enzymes, or ions of tissue microenvironment can damage the nanocarrier, causing dissociation before cellular entry.
Internalization	Cell specificity. Cellular uptake via endocytosis.
Intracellular	Escape from endosomal compartment. Dissociation from the nanocarrier in the cytoplasm to release siRNA or miRNA cargo.