Journal of Aging Research [101]. In addition, let-7 expression is downregulated in other cancer types such as hepatocellular carcinoma, melanoma, and nasopharyngeal carcinoma. Let-7 acts by suppressing protein expression of several genes such as high mobility group AT-hook 2 (HMGA2), Myc, CCND1, and BCL2-like 1 (BCL-XL) [102–106]. Functional studies using cultured lung cancer cells and mouse models of lung cancer have shown that administration of let-7 mimics blocks the proliferation of cancer cells and reduces the growth of lung tumors, respectively [107–109]. Moreover, in hepatocellular carcinoma cells, the transfection of a let-7 family member, let-7g mimics, inhibits cell proliferation by downregulating the oncogene, c-Myc, and upregulating the tumor suppressor gene, p16INK4A [110]. miRNA replacement is also demonstrated by miR-34a [111], which is underexpressed in multiple cancer types. miR-34a, a key eﬀector of the p53 signaling pathway, induces apoptosis, G2 arrest, and senescence in cancer cell lines by repressing the expression of direct targets, such as cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), CCND1, SIRT1, cyclin E2 (CCNE2), E2F transcription factor 3 (E2F3), neuroblastoma-derived Myc (MYCN), and B-cell CLL/lymphoma 2 (BCL2) [42, 46, 112–114]. One of the major problems for the use of miRNAs as therapeutic molecules relates to the tissue-speciﬁc delivery and cellular uptake of suﬃcient amounts of synthetic oligonucleotides to achieve sustained target inhibition [115]. Consequently, strategies have been developed to deliver miRNA-based therapeutics, including viral and nonviral vector systems. Viral vector-systems have high gene transfer eﬃciency but have limitations due to their lack of tumor- targeting capability and to residual viral elements that can be immunogenic, cytopathic, or recombinogenic. However, adenovirus-associated vectors (AAVs) do not integrate into the genome and are eﬃciently eliminated with minimal toxicity as shown in Phase I and Phase II clinical trials [13]. Furthermore, systemic administration of mir-26a using an AAV in an animal model of hepatocellular carcinoma results in apoptosis induction and signiﬁcant protection from disease progression without toxicity [116]. On the other hand, nonviral vector systems include cationic liposome- mediated, nanoparticle-mediated, and polymer-mediated gene transfer systems for in vivo human therapy [117–119]. 5. 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