Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and small interfering RNAs (siRNAs) are important players in the control of gene regulation and represent novel promising therapeutic targets or agents for the treatment of various diseases. While synthetic ncRNAs are predominately utilized, the effects of excessive artificial modifications on higher-order structures, activities and toxicities of ncRNAs remain uncertain. Inspired by recombinant protein technology allowing large-scale bioengineering of proteins for research and therapy, efforts have been made to develop practical and effective means to bioengineer ncRNA agents. The fermentation-based approaches shall offer biological ncRNA agents with natural modifications and proper folding critical for ncRNA structure, function and safety. In this article, we will summarize current recombinant RNA platforms to the production of ncRNA agents including siRNAs and miRNAs. The applications of bioengineered ncRNA agents for basic research and potential therapeutics are also discussed.

Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome-derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer-related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA-based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.

Altered metabolism, such as aerobic glycolysis or the Warburg effect, has been recognized as characteristics of tumor cells for almost a century. Since then, there is accumulating evidence to demonstrate the metabolic reprogramming of tumor cells, addiction to excessive uptake and metabolism of key nutrients, to support rapid proliferation and invasion under tumor microenvironment. The solute carrier (SLC) superfamily transporters are responsible for influx or efflux of a wide variety of xenobiotic and metabolites that are needed for the cells to function, as well as some medications. To meet the increased demand for nutrients and energy, SLC transporters are frequently dysregulated in cancer cells. The SLCs responsible for the transport of key nutrients for cancer metabolism and energetics, such as glucose and amino acids, are of particular interest for their roles in tumor progression and metastasis. Meanwhile, rewired metabolism is accompanied by the dysregulation of microRNAs (miRNAs or miRs) that are small, noncoding RNAs governing posttranscriptional gene regulation. Studies have shown that many miRNAs directly regulate the expression of specific SLC transporters in normal or diseased cells. Changes of SLC transporter expression and function can subsequently alter the uptake of nutrients or therapeutics. Given the important role for miRNAs in regulating disease progression, there is growing interest in developing miRNA-based therapies, beyond serving as potential diagnostic or prognostic biomarkers. In this article, we discuss how miRNAs regulate the expression of SLC transporters and highlight potential influence on the supply of essential nutrients for cell metabolism and drug exposure toward desired efficacy.

Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and small interfering RNAs (siRNAs) are important players in the control of gene regulation and represent novel promising therapeutic targets or agents for the treatment of various diseases. While synthetic ncRNAs are predominately utilized, the effects of excessive artificial modifications on higher-order structures, activities and toxicities of ncRNAs remain uncertain. Inspired by recombinant protein technology allowing large-scale bioengineering of proteins for research and therapy, efforts have been made to develop practical and effective means to bioengineer ncRNA agents. The fermentation-based approaches shall offer biological ncRNA agents with natural modifications and proper folding critical for ncRNA structure, function and safety. In this article, we will summarize current recombinant RNA platforms to the production of ncRNA agents including siRNAs and miRNAs. The applications of bioengineered ncRNA agents for basic research and potential therapeutics are also discussed.

The discovery of functional small noncoding RNAs (ncRNAs), such as microRNAs and small interfering RNAs, in the control of human cellular processes has opened new avenues to develop RNA-based therapies for various diseases including viral infections and cancers. However, studying ncRNA functions and developing RNA-based therapeutics relies on access to large quantities of affordable ncRNA agents. Currently, synthetic RNAs account for the major source of agents for RNA research and development, yet carry artificial modifications on the ribose ring and phosphate backbone in sharp contrast to posttranscriptional modifications present on the nucleobases or unmodified natural RNA molecules produced within cells. Therefore, large efforts have been made in recent years to develop recombinant RNA techniques to cost-effectively produce biological RNA agents that may better capture the structure, function, and safety properties of natural RNAs. In this article, we summarize and compare current in vitro and in vivo methods for the production of RNA agents including chemical synthesis, in vitro transcription, and bioengineering approaches. We highlight the latest recombinant RNA approaches using transfer RNA (tRNA), ribosomal RNA (rRNA), and optimal ncRNA scaffold (OnRS), and discuss the applications of bioengineered ncRNA agents (BERAs) that should facilitate RNA research and development.

Accumulating evidence has demonstrated that genome-derived noncoding RNAs (ncRNAs) play important roles in modulating inter-individual variations observed in drug metabolism and disposition by controlling the expression of genes coding drug metabolizing enzymes and transporters (DMETs) and relevant nuclear receptors (NRs). With the understanding of novel ncRNA regulatory mechanisms and significance in the control of disease initiation and progression, RNA-based therapies are under active investigation that may expand the druggable targets from conventional proteins to RNAs and the genome for the treatment of human diseases. Herein we provide an overview of research strategies, approaches and their limitations in biochemical and pharmacological studies pertaining to ncRNA functions in the regulation of drug and nutrient metabolism and disposition, and discussion on the promise and challenges in developing RNA therapeutics.

Multidrug resistance (MDR) is a serious problem that hampers the success of cancer pharmacotherapy. A common mechanism is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) that limit the exposure to anticancer drugs. One way to overcome MDR is to develop ABC efflux transporter inhibitors to sensitize cancer cells to chemotherapeutic drugs. The complete clinical trials thus far have showen that those tested chemosensitizers only add limited or no benefits to cancer patients. Some MDR modulators are merely toxic, and others induce unwanted drug-drug interactions. Actually, many ABC transporters are also expressed abundantly in the gastrointestinal tract, liver, kidney, brain and other normal tissues, and they largely determine drug absorption, distribution and excretion, and affect the overall pharmacokinetic properties of drugs in humans. In addition, ABC transporters such as P-gp, MRP1 and BCRP co-expressed in tumors show a broad and overlapped specificity for substrates and MDR modulators. Thus reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development. In this review, we provide an overview of the role of ABC efflux transporters in MDR and pharmacokinetics. Preclinical assays for the assessment of drug transport and development of MDR modulators are also discussed.