Preface: A new era of RNA-based therapies

Abstract

The global impact of the first two FDA-authorized mRNA vaccines on COVID-19 outbreaks has brought new chances for profits to different classes of RNA-based therapeutics, including mRNA, miRNA, and siRNA. More than a half-century after the discovery of RNA, RNA drugs are finally in the midst of a therapeutic renaissance. The number of RNA-based therapeutics under development and clinical trials is growing faster than ever. This rapid growth of RNA drugs is due to solving the issues of stability, target specificity, delivery, and immunogenicity [1]. There is still room for technological innovation in each of these areas. Small biotech startups and academic labs have also been propagating transformative ideas very recently.

This special issue entitled “A new era of RNA-based therapies” has captured the dynamic and rapidly evolving field of RNA therapeutics, showcasing a range of pioneering research that illuminates the current state and future potential of this domain. From the significant advancements in lipid nanoparticles (LNPs) for RNA delivery highlighted by Prof. Hyukjin Lee et al. to the exploration of gene editing techniques by Dr. Kunwoo Lee et al., each article has contributed to a deeper understanding of the challenges and opportunities in RNA-based treatments. The issue comprehensively addressed various aspects such as mRNA in cancer immunotherapy, siRNA in treating Alzheimer’s disease, and the intricacies of delivery systems and safety concerns. The contributions of Prof. Kanjiro Miyata et al. and Prof. Xiuling Lu et al. underscored the importance of balancing safety, stability, and efficiency in RNA therapeutic delivery. This collection of works not only reflects the current technological and scientific strides in RNA therapeutics but also sets the stage for future innovations and applications in this promising and transformative field of medicine.

The review article from Prof. Hyukjin Lee and co-workers [2] discussed the significant role of LNPs in RNA therapeutics, particularly highlighted by the success of COVID-19 mRNA vaccines. They addressed the challenges in efficient RNA delivery, notably LNPs' limitations like targeted delivery and reduced potency over repeated doses. The review explored LNPs' fundamentals, recent advancements, and potential breakthrough technologies for future applications, contributing to the evolving landscape of RNA-based therapies.

In their review, Dr. Kunwoo Lee and colleagues [3] examined the therapeutic potential of gene editing, especially using mRNA delivery for systems like CRISPR-Cas and base editors. The review emphasized improvements in gene editing technology and explored both ex vivo and in vivo techniques.

Dr. Soo Hyeon Lee and team [4] emphasized the potential of mRNA in cancer immunotherapy. This review tackled the inherent challenges associated with mRNA therapy, such as stability, delivery efficiency, and variable expression. It spotlighted recent advancements in chemical modifications and delivery systems, enhancing the efficacy of mRNA in cancer treatment.

The review article of Dr. Yoosoo Yang and co-workers [5] illuminated the significant role of mRNA, particularly in treating malignant tumors. Highlighting advancements in mRNA and nanoformulation-based delivery technologies, the article underscored mRNA's vast potential in cancer immunotherapy. It explored various therapeutic applications of mRNA, such as cancer vaccines, adoptive T-cell therapies, therapeutic antibodies, and immunomodulatory proteins, offering a thorough overview of current strategies in mRNA-based treatments.

The review article by Prof. Rakesh Tiwari et al. [6] focused on siRNA as a treatment for Alzheimer’s disease (AD). The article reviewed the latest in AD pathophysiology, clinical trials, and siRNA approaches, especially addressing the challenges of crossing the blood？brain barrier.

Dr. Sun Hwa Kim and colleagues' article [7] focused on advancing RNA interference (RNAi) therapeutics beyond liver-targeted diseases. They highlighted the need for better delivery systems to target tumors and major organs, discussing the challenges in clinical trials and innovative preclinical platforms for treating extrahepatic diseases.

Prof. Yizhou Dong and co-workers [8] delved into the advancements of in vitro transcribed mRNA (IVT mRNA) for clinical applications. It highlighted IVT mRNA's role in rapidly developing therapeutics for various diseases, including cancer and gene editing, focusing on its optimization and diverse applications. The article emphasized IVT mRNA's potential as a safe and effective treatment for both emerging and existing diseases.

In their review, Prof. Jean-Christophe Leroux and colleagues [9] focused on the challenges of delivering RNA therapeutics, especially the issue of endosomal escape. They reviewed various strategies, including cell-penetrating peptides and pore-forming proteins, to enhance endosomal escape for RNA drugs. Despite some advancements, these methods often confronted challenges like low efficiency, toxicity, and immunogenicity. The review paper highlighted the importance of rigorous testing and precise quantification in future research.

Prof. Kanjiro Miyata and co-workers [10] explored the challenges of balancing safety and stability in RNA therapeutic delivery using polymer-based systems. Their review paper highlighted the need for improved designs to address issues like immune responses and controlled RNA release. The study emphasized a biological approach over material chemistry in advancing polymer delivery systems for RNA therapeutics.

Prof. Xiuling Lu et al.'s [11] review focused on the toxicity of siRNAs in therapeutic use. It examined the challenges in siRNA design related to safety and toxicity, which impact clinical trials. The review analyzed both intrinsic and delivery-related toxicities, discussing strategies for safer siRNA therapeutics and highlighting the need for comprehensive safety assessments and high-throughput screening of siRNA drugs and their delivery systems.

This special issue on RNA-based therapies has marked a significant moment in medical research, signaling a future rich with potential. It provided a detailed exploration of recent progress in mRNA and siRNA technologies, alongside a thorough analysis of delivery systems and safety profiles. It highlighted a shift in medicine, utilizing RNA science to tackle complex health issues. As the field progresses, the integration of innovation and practical application will likely shape the development of RNA therapeutics, making them a key element in modern medical treatments. This collection of reviews will serve as a guide for both current and future work in RNA therapeutics.