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Breakthroughs in mRNA modification and nanoparticle-based delivery vehicles facilitate gene therapy strategies

mRNA-based therapy is a unique and promising technique to prevent and cure many diseases associated with cell genetic components. Unlike DNA-based therapies, mRNA molecules do not require access to the nucleus. Therefore, there is no risk of genomic integration. Protein expression is also transient and may be fine-tuned. However, the mRNA molecule is large and naturally fragile, making it sensitive to RNase breakdown. Furthermore, mRNA is an intrinsic TLR3/7 signaling agonist that activates the innate immune system and generates several unpleasant side effects. In the past, these limitations limited the use of mRNA as a therapeutic agent. Recent breakthroughs in mRNA modification and nanoparticle-based delivery vehicles have overcome these challenges. As evidenced by mRNA vaccines in clinical trials and, more recently, COVID-19 mRNA vaccines, the utilization of polyplexes, lipoplexes and LPPs has led to the product development and clinical usage of mRNA-based therapeutics. Besides cell reprogramming and gene editing, mRNA-based therapies have been applied in many other scientific sectors. However, difficulties such as optimizing delivery route, transfection efficiency, optimizing combination therapy, and considering toxicity remain unsolved for widespread clinical uses. The delivery technique can impact all recipient cells, antigen presentation efficacy, and overall responsiveness to mRNA therapy. Although preclinical research shows great transfection efficiency in many scenarios, transfection efficiency remains a restriction for human mRNA delivery. In clinically implementing innovative medicines, toxicity is always a key concern. Even a small side effect may affect the outcome of the therapeutic application. Combining mRNA-based treatment with various therapeutic techniques like immune-checkpoint inhibitors, chemotherapy, and radiation is a promising strategy to increase therapeutic efficacy. However, for the best therapeutic impact, the dosage and dosing schedule should be fine-tuned.