The present disclosure provides methods and compositions for enhanced delivery of siRNA or miRNA, into the interior of multilayered tissues, and into the cytoplasm or nucleus of cells of a tissue. Such methods and compositions yield tumor-selective and intracellular delivery of RNAi agents and allow for RNAi-mediated activity such as knock-down of the target genes and associated products. The current disclosure further provides methods and compositions for improving the intracellular bioavailability of nucleotide agents.