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Recent Advances in RNA-Based Therapeutics: Mechanisms, Strategies, and Future Directions

RNA-based therapeutics have revolutionized medicine by offering new possibilities for treating previously intractable diseases[1]. The field encompasses multiple modalities—antisense oligonucleotides (ASOs), RNA interference (RNAi), messenger RNA (mRNA), and emerging RNA editing technologies—each with distinct mechanisms and therapeutic applications. By precisely regulating gene expression or directly encoding therapeutic proteins, RNA therapeutics provide innovative treatment strategies for conditions that are difficult to address with traditional small-molecule or protein-based drugs[2].
In this issue, we focus on three key areas: an overview of various types of RNA therapeutics and their mechanisms of action; strategies to improve the delivery efficiency of RNA therapeutics; and the challenges and future directions for enhancing their safety, efficacy, and translational potential.
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The Technical Platforms and Mechanisms of RNA Therapeutics
Strategies for Improving the Delivery Efficiency of RNA Therapeutics
Challenges and Future Prospects of RNA Therapeutics
The Technical Platforms and Mechanisms of RNA Therapeutics
Strategies for Improving the Delivery Efficiency of RNA Therapeutics
Challenges and Future Prospects of RNA Therapeutics
The Technical Platforms and Mechanisms of RNA Therapeutics
RNA can achieve therapeutic effects by regulating gene expression, mainly encompassing strategies to enhance gene expression (e.g., RNA activation (RNAa) and mRNA therapy), suppress gene expression (e.g., RNAi and ASOs) and other RNA-based therapeutic approaches (e.g., aptamers and CRISPR-Cas systems).
Figure 1. The mechanisms underlying RNA-based therapies[3].
Strategy to Enhance Gene Expression
RNAa (srRNA): Self-replicating RNA (srRNA) is a technique derived from positive-strand RNA viruses. The principle involves retaining the non-structural protein (NSP) genes necessary for virus replication, while replacing the structural protein genes with exogenous therapeutic genes (such as vaccine antigens or therapeutic proteins). Once inside the cytoplasm, srRNA uses its own replication enzymes to undergo exponential amplification, thereby achieving high-level and long-duration protein expression at extremely low doses[4].
mRNA therapy: mRNA therapy represents a more "direct" approach. Its core lies in delivering in vitro-synthesized mRNA molecules that encode the required proteins into the cytoplasm. Using the host cell’s ribosomes, these mRNA molecules are directly translated to produce functional proteins, thereby compensating for genetic defects or providing therapeutic functions. The popularity of mRNA therapy stems from the successful development of COVID-19 mRNA vaccines (BNT162b2, Pfizer-BioNTech; and mRNA-1273, Moderna), but its applications have since expanded to diverse areas such as cancer and autoimmune diseases[5]. Currently, RNA drugs are usually delivered using liposomes.
Strategy to Suppress Gene Expression
RNAi (siRNA and miRNA): RNAi therapy is based on a natural biological process in which RNA sequences inhibit the expression of specific proteins encoded by DNA. RNAi molecules bind to mRNA that encode specific proteins and direct them to the RNA-induced silencing complex (RISC), which then cleaves the mRNA, thereby preventing the production of the corresponding proteins[6].
● Small interfering RNA (siRNA) is a double-stranded RNA molecule, usually consisting of 20-25 nucleotides. In the RNAi pathway, siRNA binds to complementary mRNA molecules, leading to sequence-specific degradation of the target mRNA and thus silencing gene expression[6]. Inclisiran is a prominent example of an siRNA-based drugs and remains the only siRNA cholesterol-lowering drug approved for global use. It was approved in China in August 2023.
● MicroRNA (miRNA) is non-coding double-stranded or single-stranded RNA molecule capable of inducing gene silencing through mRNA degradation or translational inhibition. Two therapeutic strategies have been developed: miRNA mimics (double-stranded) and miRNA inhibitors (single-stranded)[6].
On July 22, 2025, the French biotech company Abivax announced positive Phase III results for its oral ulcerative colitis drug, Obefazimod. This success marks the world's first clinical validation of a miRNA therapy for an autoimmune disease and represents a major step toward translating the Nobel Prize-winning miRNA research into practical treatment.
Antisense oligonucleotides (ASOs): ASOs are chemically synthesized oligonucleotides designed to bind to the target RNA sequences through the Watson-Crick hybridization process and base pairing rules. They exert their therapeutic effects mainly by blocking translation via steric hindrance or by recruiting RNase H1 to degrade the target mRNA[6]. The world's first drug for spinal muscular atrophy, Nusinersen, achieved global sales of USD 1.951 billion in 2021, making it the highest-selling small nucleic acid drug of that year.
Strategy to Edit Gene Expression
Clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing enables the direct modification of target RNA sequences to treat specific disorders[7].
Strategies for Improving the Delivery Efficiency of RNA Therapeutics
RNA-based drugs have received extensive attention. The abundant RNA molecules can target specific proteins, transcripts, and genes, thereby expanding the potential targets for drug development. However, several challenges still hinder the broader clinical application of current RNA therapies. Researchers have explored various strategies, such as chemical modification of RNA molecules, optimization of delivery systems, conjugation of RNA drugs with targeting ligands, incorporation of stimulus-responsive elements, and development of novel nanocarriers to enhance stability, tissue targeting, cellular uptake, and the safety of RNA therapies.
Chemical Modification
By chemically modifying the RNA "cargo" itself, it can be made more suitable for delivery and optimized for proper function.
Figure 2. Chemical modifications used for small nucleic acids[8].
Common modifications can be divided into three categories: ribosome modifications, nucleobase modifications, and backbone modifications. Modifications of ribosomes are typically performed at the 2' position of the ribose sugars (blue box) and sugar chains (orange box). In modifications of the base group, uracil, adenine and cytosine are the common objects (purple box), and the ribose sugar can be completely replaced (red box). Backbone modifications involve altering the PO linkage, including the nonbridging oxygen atom (cyan box), 3'-bridging oxygen atom (green box), and the entire PO linkage (golden box), which reduces the net anionic charge of small nucleic acids.
Optimization of Delivery Vehicles
Optimizing the delivery system is the most crucial strategy to address issues of RNA stability, targeting, and intracellular release. Scientists have developed a variety of delivery systems, including both viral and non-viral methods. Here, we focus on several representative delivery strategies.
Figure 3. Schematic illustration of LNP and its chemical composition of four main components[9].
Lipid nanoparticles (LNPs) are currently the most promising delivery carriers, composed of ionizable (or cationic) lipids, helper lipids, cholesterol, and PEGylated lipids. Ionizable lipids bind and encapsulate the negatively charged RNA, enhancing stability, cellular uptake, and endosomal release. Helper lipids and cholesterol provide structural support, while PEG-lipids prolong circulation time and reduce clearance. LNPs have been successfully used to deliver siRNA for transthyretin amyloidosis (ATTR) and are being explored for oncology, rare genetic diseases, and refractory disorders.
Figure 4. Schematic diagram of exosome delivery[10].
Exosomes are natural extracellular vesicles (typically 30-150 nm) with a lipid bilayer structure, generated via the endosomal pathway: early endosomes mature into late endosomes and subsequently into multivesicular bodies (MVBs), which release exosomes upon fusion with the plasma membrane. Their cellular origin gives them high biocompatibility, low immunogenicity, and efficient delivery capabilities. MCE provides an exosome compound library, enabling researchers to flexibly select and combine compounds for their experiments. In addition, MCE offers a variety of kits for exosome isolation, lysis, and protein extraction.
Targeted Ligand Conjugation
By enhancing the "homing" ability of the carrier to target tissue or cells, the accumulation in non-target tissues (off-target effect) can be minimized. Here, we introduce the specific ligands on two important carrier surfaces.
Figure 5. Cell type-specific aptamer for targeted therapy[11].
Aptamers are short, single-stranded DNA or RNA oligonucleotides (typically 20-80 nucleotides) that fold into unique 3D structures, allowing high-affinity binding to specific targets. Often referred to as “chemical antibodies”, aptamers offer advantages such as small size, high stability, ease of chemical synthesis, and the ability to target a wide range of molecules. Pegaptanib (Macugen) is the first FDA-approved aptamer drug, used for age-related macular degeneration (AMD) by targeting VEGF165.
Figure 6. CPPs as cargo carriers for targeted delivery [12].
Cell-penetrating peptides (CPPs) and homing peptides are short chains of 5-30 amino acids that enhance nucleic acid delivery. Compared with viral vectors, these peptides provide superior biocompatibility and payload capacity. Rationally designed CPPs can overcome key biological barriers, such as cellular uptake and endosomal escape, thereby improving delivery efficiency. While some preclinical studies and clinical investigations are ongoing, no CPP-based RNA drugs have yet received FDA approval.
Challenges and Future Prospects of RNA Therapeutics
Figure 7. Timeline of milestones from the discovery of small nucleic acid drugs to their clinical use[8].
The development of RNA therapeutics has been marked by substantial technological advances, pivotal drug approvals, and notable setbacks. A timeline highlighting key breakthroughs illustrates the evolution from foundational research to clinical application. As the performance of ASOs has improved, the scope of therapeutic opportunities has broadened, now encompassing both rare and common diseases and virtually any route of administration.
Figure 8. The challenges and future directions of small nucleic acid drugs[8].
Despite significant progress, small nucleic acid therapeutics still face fundamental challenges that limit their full potential. Financial and time constraints remain major barriers due to the prohibitively expensive and lengthy process from discovery to clinic. Safety profiles are further complicated by unintended immune reactions, where the therapeutic oligonucleotides or their chemical modifications can provoke immunotoxicity. Additionally, nanoparticle toxicity introduces significant uncertainty, as the potential for organ-specific damage and poorly understood long-term effects of delivery vehicles remain critical concerns. To overcome these limitations, research is actively advancing along several key fronts.
Future Directions for Small Nucleic Acid Therapeutics
Artificial Intelligence in Drug Discovery is being leveraged to address high costs and development complexity. Platforms such as TREAT and MysiRNA utilize machine learning for target identification and optimization of siRNA/ASO sequences, while the AGILE platform applies deep learning to design novel ionizable lipids for LNPs, collectively accelerating discovery and improving predictive accuracy.
Vector Screening and Surface Modifications are advancing through systematic approaches. High-throughput screening of nanoparticle libraries, including evaluation of over 1,000 LNP formulations and 720 biodegradable lipids, helps identify optimal delivery vehicles. Moreover, strategies such as incorporating selective organ-targeting (SORT) molecules into LNPs and conjugating targeting ligands like RGD and RVG peptides are employed to achieve targeted delivery beyond the liver.
Improved Safety Profiles are being pursued by mitigating the immunogenicity of both the delivery vector and the nucleic acid drug. For nanoparticles, surface modifications with PEG or encapsulation in cell membranes help reduce immune recognition and toxicity. For the oligonucleotides themselves, optimizing sequence selection and introducing chemical modifications such as 2'-F/Me are key strategies to minimize off-target effects and immune activation.
Rational Target Selection and Off-Target Effect (OTE) Reduction are foundational to developing precise therapies. This involves using advanced genomic tools, such as next-generation sequencing (NGS), for target identification and employing computational algorithms, including OligoWalk and AttSiOff, to predict and mitigate potential off-target effects during the initial design phase of nucleic acid sequences.
Discovery of Novel Nucleic Acid Systems is expanding the therapeutic toolbox through fundamental innovation. Research is developing novel chemistries, such as thiourea-based nucleic acids (TNA) for enhanced nuclease resistance, as well as advanced structural frameworks, including tetrahedral framework nucleic acids (tFNAs) and "caged-siRNA" structures, offering new platforms for stable and efficient delivery.
Summary
RNA therapeutics are reshaping modern medicine, offering powerful ways to enhance, silence, or edit genes. From mRNA vaccines to RNAi, antisense oligonucleotides, and CRISPR-based tools, these technologies target diseases that were once difficult to treat. Advances in delivery methods—like LNPs, exosomes, and targeted ligands—improve stability, precision, and cellular uptake. While challenges remain, including safety, immune reactions, and off-target effects, innovations such as AI-guided design, high-throughput screening, and new nucleic acid chemistries are rapidly expanding the potential of RNA-based therapies across genetics, neurology, oncology, and beyond.
Recommended siRNA Products
Product Name Cat. No. Feature/Disease
Inclisiran sodium HY-132591A Cholesterol-lowering agent, used for arteriosclerosis of the heart and blood vessels
SiRNA Negative Control HY-150150 A commonly used negative control in the literature
Patisiran sodium HY-132609 Used for the polyneuropathy caused by hereditary transthyretin amyloidosis (hATTR)
Givosiran sodium HY-132610A Used for acute hepatic porphyria
Fitusiran sodium HY-132587A Increases thrombin generation and has the potential for the research of the hemophilia
Elebsiran sodium HY-147266 Used for chronic hepatitis B and hepatitis D
Cy3-siRNA Negative Control HY-150150F Used for easy visualization and assessment of transfection efficiency
Lumasiran sodium HY-132613 Used for congenital hyperoxaluria
ATU027 sodium HY-153482A Used for advanced or metastatic pancreatic adenocarcinoma
Note: MCE can provide products for research use only. We do not sell to patients.
Recommended LNPs Products
Product Name Cat. No. Feature/Disease
PEG2000-C-DMG HY-145411 A PEG-modified lipid that can be used for the preparation of Onpattro
D-Lin-MC3-DMA HY-112251 An ionizable cationic lipid
ALC-0159 HY-138300 A commonly used PEG-modified lipid
SM-102 HY-134541 An amino cationic lipid
ALC-0315 HY-138170 An electrolytically dissociable amino lipid
DOTAP chloride HY-112754A An ionizable cationic lipid
5A2-SC8 HY-145799 An electrolytically dissociable amino lipid
POPG sodium salt HY-130463 A phospholipid with negative charge, used for Parkinson's disease
Liposome Library HY-L214 Compound library containing 136 liposome compounds, which is a good tool for lipidomic-related studies.
Note: MCE can provide products for research use only. We do not sell to patients.