Development of microRNA (miRNA or miR) based treatments such as miR-34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. In recent work published by a team of scientists led by researchers from UC Davis, investigators presented a new approach to high-yield and large-scale biosynthesis of chimeric miR-34a agent in Escherichia coli using tRNA scaffold, which may act as a prodrug for cancer therapy. In their study, investigators quickly purified the recombinant tRNA fusion pre-miR-34a (tRNA/mir-34a) to a high degree of homogeneity (> 98%) using anion-exchange fast protein liquid chromatography (FPLC), whose primary sequence and posttranscriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed favorable cellular stability while it was degradable by several ribonucleases. Through LC Sciences’ small RNA sequencing service and qPCR studies, it was revealed that tRNA-carried pre-miR-34a was precisely processed to mature miR-34a within human carcinoma cells, whereas the same tRNA fragments were produced from tRNA/mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of varoius types of human carcinoma cells in a dose dependent manner and to much greater degrees than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, it was shown that tRNA/mir-34a significantly suppressed the growth of human non-small cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared to the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effects on blood chemistries and IL-6 levels in mouse models, suggesting that recombinant RNAs were well tolerated. Their findings provoke a conversation on producing biological miRNAs to perform miRNA actions, and point towards a new direction to develop miRNA-based therapies.