RNA therapeutics, including mRNA, siRNA, miRNA, antisense oligonucleotides (ASOs), RNA aptamers and CRISPR-related RNA tools, possess exceptional advantages over traditional small-molecule drugs. They can precisely regulate gene expression at the molecular level and target previously “undruggable” genes, opening new avenues for treating complex illnesses. Despite remarkable breakthroughs in basic research and clinical applications, the widespread use of RNA drugs is still severely constrained by inherent limitations. Foremost among these are RNA instability caused by enzymatic degradation, poor cellular uptake, and a series of formidable in vivo biological barriers including rapid renal clearance, phagocytosis by immune cells, and endosomal entrapment after cell entry. Off-target effects and unwanted immunogenicity also remain major safety and efficacy concerns for researchers worldwide.
To address these obstacles, the review systematically summarizes two major technical solutions: chemical modification of RNA molecules and the development of advanced delivery systems. For RNA structural modification, multiple mature strategies are elaborated, covering ribose modification (2'-OMe, 2'-F, 2'-MOE), phosphate backbone modification, base modification (pseudouridine, m1ψ etc.), and terminal (5' cap and 3' poly(A) tail) modification. These chemical alterations effectively enhance RNA stability, resist nuclease degradation and reduce immune responses.
In terms of delivery carriers, non-viral vectors have become the mainstream choice due to superior safety profiles. The paper details four primary categories: lipid nanopreviews (LNPs), polymeric nanopreviews (PNPs), extracellular vesicles (EVs) and inorganic nanocarriers. Among them, LNPs stand out as the most clinically validated platform, with multiple LNP-formulated RNA drugs and vaccines already approved for market. Meanwhile, artificial intelligence and machine learning are emerging as powerful auxiliary tools, capable of optimizing RNA sequence design, screening high-performance lipid materials, predicting drug biodistribution and toxicity, and greatly boosting the efficiency of RNA therapeutic research and development.
The review also presents a detailed landscape of clinical development for RNA therapeutics, categorizing approved candidates and pipeline products by disease areas: cancer, infectious diseases, neurological disorders, hepatic and metabolic diseases, genetic disorders, and pulmonary diseases. Approved products such as mRNA COVID-19 vaccines, the siRNA drug Patisiran and ASO therapy Nusinersen have demonstrated solid clinical value. A large number of investigational agents, including tumor neoantigen mRNA vaccines, antiviral RNAi drugs and gene-editing therapeutics, are now in different phases of clinical trials, showing broad application prospects.
The review points out that although RNA therapeutics have achieved remarkable milestones, challenges including large-scale standardized production, product consistency, pharmacokinetic optimization and long-term biosafety still need to be resolved. Looking ahead, the integration of multiple cutting-edge technologies will further break existing limits. It is expected that more RNA-based drugs will enter the market in the future, providing more precise and personalized treatment options for patients with intractable diseases.
This landmark review, titled
Harnessing RNA molecules for therapy: advances in design, delivery, and clinical development, was published online on November 19, 2025, in
Targetome (Volume 1, Issue 1).
doi: 10.48130/targetome-0025-0003