Figure 6 summarizes the various constraints to miRNA delivery. For instance, poor miRNA penetration is caused by the leaky nature of aberrant tumor vasculature (215). The rapid cleavage of naked miRNAs by serum nucleases of the RNase A type poses another challenge (216). Additionally, there is a rapid renal clearance, notably for naked miRNA (217). When utilizing big NPs (>100 nm), reticuloendothelial system (RES) clearance would rise in the liver, spleen, lung, and bone marrow, leading to nonspecific absorption by innate immune cells such monocytes and macrophages (218). This evidence concerns the gene RNASE1 and neoplasm.