RNA editing is redefining the frontiers of molecular medicine by enabling precise, reversible modifications to RNA transcripts without altering the underlying DNA. Building on decades of foundational biology, recent breakthroughs in enzyme engineering, delivery technologies, and synthetic guide design have brought the field to the threshold of clinical application. Therapeutic RNA editing holds particular promise for rare genetic diseases, neurodegenerative conditions, and other complex disorders, thanks to its ability to modulate gene expression with temporal control and high specificity. Compared to genome editing, RNA editing offers reduced risk of permanent off-target effects and enables allele-specific interventions. As biotech innovators and major pharmaceutical players enter the space, investment is accelerating, but challenges remain around delivery, regulatory frameworks, and scalability. Still, RNA editing is poised to become a powerful pillar in the next generation of precision therapeutics.
A New Chapter in Molecular Medicine
Over the past decade, the life sciences have witnessed a profound expansion in the toolbox of genomic and transcriptomic engineering. While technologies like CRISPR-Cas9 have revolutionized gene editing by enabling precise alterations to DNA, an equally transformative field has been gaining momentum: RNA editing. As a posttranscriptional process, RNA editing modifies RNA molecules after they are transcribed from DNA, allowing for the correction, reprogramming, or enhancement of gene expression without permanently altering the genome itself.
The therapeutic potential of RNA editing lies in its ability to target specific transcripts transiently and with high precision. Unlike DNA editing, which introduces irreversible changes, RNA editing offers a reversible approach — enabling temporal control, reducing the risk of off-target genetic alterations, and potentially improving safety profiles. This has made it particularly attractive for treating genetic diseases where lifelong correction may not be necessary or where minimizing unintended consequences is paramount. Moreover, the ability to modulate RNA directly opens new therapeutic pathways for diseases that are not readily addressed by traditional gene or protein therapies, including certain neurological, metabolic, and inflammatory conditions.
As a platform, RNA editing sits at the intersection of molecular biology, synthetic biology, and advanced drug delivery. While the concept has existed for decades, breakthroughs in understanding RNA editing enzymes and the development of programmable editing systems have only recently propelled the field into clinical relevance. Emerging RNA-editing therapeutics are beginning to reach preclinical and clinical stages, prompting increased interest from biotech startups, pharmaceutical companies, and investors alike.
Origins and Mechanisms of RNA Editing
Historical Background
RNA editing emerged as a biological curiosity in the 1980s, when researchers discovered that RNA transcripts could differ from the genetic instructions encoded in DNA. One of the earliest and most striking examples came from studies of mitochondrial RNA in trypanosomes, where large-scale insertions and deletions of uridine (U) residues were found to be essential for creating functional mRNAs. This process, mediated by guide RNAs (gRNAs), revealed that genetic information could be dynamically altered after transcription — challenging the previously rigid conception of the central dogma of molecular biology.1
Shortly thereafter, the phenomenon was also observed in mammals, though in a more subtle and targeted form. In this context, adenosine-to-inosine (A-to-I) editing was identified as a key mechanism, particularly prevalent in the central nervous system. Inosine, which is read as guanosine (G) by the cellular machinery, can alter codons and thus protein sequences, or influence splicing and RNA stability. These discoveries prompted a deeper investigation into the enzymatic machinery responsible for RNA editing.
Two families of enzymes have been most closely associated with endogenous RNA editing: adenosine deaminases acting on RNA (ADARs), which catalyze A-to-I editing, and the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like family (APOBECs), primarily responsible for cytidine-to-uridine (C-to-U) conversions. ADARs are now understood to be critical regulators of neuronal function and innate immunity, while APOBEC enzymes, originally characterized for their role in lipid metabolism, have broader implications in RNA editing and innate antiviral defense.2,3
Molecular Mechanisms
Among the different forms of RNA editing, A-to-I editing by ADARs is by far the most widespread and functionally significant in humans. This process requires the presence of double-stranded RNA (dsRNA) regions, typically formed by base pairing within or between RNA molecules. ADARs bind these regions and catalyze the hydrolytic deamination of adenosine to inosine. Because cellular machinery interprets inosine as guanosine during translation and splicing, this modification can lead to changes in the encoded protein, alter splice site recognition, or affect RNA localization and turnover.2,4
Another mechanism, C-to-U editing, is catalyzed by APOBEC1 and related enzymes. Though less common in humans, it has notable biological effects, including the production of different isoforms of apolipoprotein B, with distinct roles in lipid transport and metabolism. APOBEC-mediated RNA editing has also been implicated in immune responses and the regulation of specific cellular transcripts.5
With advances in synthetic biology and molecular engineering, researchers have begun developing programmable RNA editing platforms. These systems typically combine a catalytically active enzyme, such as ADAR2, with a gRNA that brings the enzyme into proximity with the desired target site through complementary base pairing. Such modular constructs allow for targeted A-to-I editing at specific RNA loci, offering a means to correct disease-causing mutations or regulate gene expression with high precision. These tools mirror the specificity of CRISPR-based DNA editing but with a key distinction: RNA editing is transient and does not alter the genome itself, offering a reversible, potentially safer therapeutic modality.4,5
Endogenous Functions of RNA Editing
RNA editing is not merely an evolutionary artifact — it plays essential roles in normal physiology and disease. In the brain, extensive A-to-I editing contributes to neuronal plasticity by modulating the function of ion channels, neurotransmitter receptors, and other synaptic proteins. The mRNA encoding the glutamate receptor subunit GRIA2, for example, is edited at a crucial site that alters calcium permeability, with deficiencies in this editing linked to neurodevelopmental and psychiatric disorders.3
Beyond the nervous system, RNA editing also fine-tunes immune responses. ADAR1 has been shown to suppress the inappropriate activation of cytosolic RNA sensors, thus preventing autoimmune reactions. Disruption of ADAR1 activity can lead to autoinflammatory diseases and heightened sensitivity to viral infections. Moreover, both the ADAR and APOBEC families have been implicated in cancer progression and response to therapy, as editing may influence tumor suppressor expression, antigen presentation, and resistance mechanisms.
Transcriptome-wide analyses have revealed that RNA editing is concentrated at specific hotspots, often within non-coding regions like introns and untranslated regions, but also in coding sequences where it can recode amino acids. The consequences of editing vary — from modulating splicing patterns and RNA stability to altering protein function in a cell type– or condition-specific manner.6 These diverse biological roles underscore RNA editing as a fundamental regulatory mechanism — and one increasingly viewed as ripe for therapeutic exploitation.
From Mechanism to Medicine – The Present State of Therapeutic RNA Editing
Technological Advances and Toolkits
The clinical viability of RNA editing has accelerated dramatically with the development of programmable editing technologies that adapt naturally occurring enzymes for therapeutic precision. Central to this progress is the engineering of ADAR-based systems, in which endogenous or exogenous ADAR enzymes are directed to specific RNA targets using short RNA guides. These guides, often designed to form a double-stranded structure with the target transcript, recruit ADAR to catalyze A-to-I editing at a predetermined site. This approach mimics the programmability of CRISPR but avoids the risk of permanent genomic alterations.4,7
Several platform technologies have emerged to harness and improve this process. LEAPER (leveraging endogenous ADAR for programmable editing of RNA), RESTORE (recruiting endogenous ADAR using antisense oligonucleotides), and SNAP-ADAR (which chemically links a guide RNA to an ADAR domain via a SNAP-tag) represent distinct strategies to localize editing activity while minimizing the need for overexpressing foreign enzymes. Each platform balances efficiency, specificity, and delivery feasibility in different ways, highlighting the diversity of design options within RNA editing therapeutics.8
In addition to these ADAR-based tools, base editing concepts have been extended to RNA using other deaminases, such as APOBEC1 or evolved ADAR variants fused to targeting domains. These tools enable either A-to-I or C-to-U conversions at single-base resolution. Some systems rely on modular architectures that combine catalytic domains with targeting motifs, such as MS2 coat proteins or Cas-derived RNA-targeting scaffolds, which further expand the range of potential edits.
Compared with antisense oligonucleotides (ASOs) or traditional mRNA therapies, RNA editing offers more durable yet still reversible modulation of transcripts. While ASOs typically induce exon skipping or degradation via RNase H, RNA editing can alter the coding sequence itself, opening therapeutic possibilities for correcting point mutations without replacing or silencing the entire transcript. Similarly, whereas mRNA therapies supply exogenous transcripts, RNA editing modifies endogenous RNA, potentially preserving native expression patterns and regulation.4,7
Clinical Applications and Pipeline Candidates
The current wave of therapeutic RNA editing is focused largely on correcting monogenic mutations that give rise to rare and otherwise intractable diseases. Neurological disorders, such as Rett syndrome and epilepsy, where single-nucleotide variants disrupt protein function, are prime targets due to their well-characterized mutations and localized transcript expression. Genetic liver diseases, such as ornithine transcarbamylase deficiency or phenylketonuria, are also being pursued due to the accessibility of hepatocytes via systemic delivery strategies and the liver’s inherent role in metabolic regulation.9,10
Biotech companies have formed the vanguard of RNA editing innovation. Shape Therapeutics has pioneered AI-guided design of RNA payloads and developed programmable ADAR systems delivered via AAV vectors. Wave Life Sciences is advancing stereopure oligonucleotide-based RNA editing candidates, including a RESTORE platform candidate for addressing alpha-1 antitrypsin deficiency. Korro Bio has focused on endogenous ADAR recruitment for hepatic diseases, while AIRNA leverages engineered RNA guides for targeted transcript correction. Each company brings a distinct technical angle, from guide RNA chemistry to delivery systems and tissue targeting.9,11
Delivery remains a critical differentiator and a major technical hurdle. Lipid nanoparticles (LNPs), which proved their utility in mRNA COVID-19 vaccines, are being repurposed for RNA editing cargo. Adeno-associated viruses (AAVs) offer high transduction efficiency but raise concerns regarding immunogenicity and payload size. Engineered extracellular vesicles, designed to mimic physiological intercellular communication, offer a promising non-viral alternative with lower immunogenic risk. The choice of delivery platform must balance tissue tropism, repeat dosing potential, and regulatory considerations.10
Strengths and Challenges
Therapeutic RNA editing presents a compelling balance of specificity and safety. Because it operates at the RNA level, edits are not permanent and thus carry a lower risk of off-target genotoxicity compared to genome-editing approaches. The ability to revert, adjust, or halt treatment provides an added layer of control, which is particularly valuable in pediatric and progressive diseases. Moreover, RNA editing enables allele-specific targeting, allowing correction of pathogenic variants while sparing wild-type alleles — an especially important consideration for dominant-negative mutations.12
However, significant challenges remain. Delivery to the appropriate cells and tissues is one of the foremost obstacles, particularly in reaching the brain, muscle, or other less-accessible organs. Off-target editing remains a concern, as even transient base changes at the wrong site can produce undesired effects if they disrupt critical regulatory or coding sequences. Immunogenicity must be closely monitored, both from delivery vehicles and the editing enzymes themselves, especially when introducing engineered or exogenous proteins. Achieving high-efficiency editing in vivo while preserving specificity is an ongoing goal of most platforms.13
Another unresolved issue is the regulatory framework under which RNA editing will be evaluated. It straddles the line between gene therapy and RNA-based therapeutics, presenting novel questions about classification, long-term monitoring, and manufacturing. As clinical trials progress, regulatory agencies will need to define appropriate standards for safety, efficacy, and quality control — especially given the diversity of editing mechanisms and delivery strategies now in development.8
Despite these challenges, the field is advancing rapidly. The first clinical data are beginning to emerge, and many RNA-editing programs are approaching the investigational new drug (IND) filing stage. As technical obstacles are overcome and the regulatory landscape matures, RNA editing appears poised to join the therapeutic mainstream as a flexible, programmable, and powerful modality for a wide range of diseases.
Emerging Frontiers and Future Directions
Next-Gen Engineering
As therapeutic RNA editing matures, the next wave of innovation is moving beyond traditional ADAR-based platforms toward more versatile and programmable systems. While ADAR enzymes have proven foundational for A-to-I editing, their sequence context preferences and reliance on endogenous expression in target tissues present limitations. To address these challenges, researchers are exploring novel deaminases, evolved or repurposed from other species, that expand the editing scope to include alternative base transitions or broader sequence compatibility.8
Synthetic biology is also playing a transformative role in advancing RNA editing technologies. Modular systems are being developed that enable conditionally responsive editing — editing only in the presence of certain cellular signals, disease markers, or environmental cues. These RNA-editing “circuits” can be designed to activate only in cancer cells, for instance, reducing the risk of off-target effects in healthy tissue. Similarly, efforts are underway to develop multiplexed editing systems capable of targeting multiple RNA sites simultaneously or sequentially, allowing for the correction of polygenic diseases or the fine-tuning of complex cellular pathways.4
Such programmable and responsive platforms could ultimately give rise to highly individualized RNA therapeutics — tools that not only correct mutations but actively interpret and respond to cellular context in real time. This shift toward context-aware, circuit-driven editing represents a fundamental expansion in the conceptual and functional scope of RNA-based medicine.
Delivery Innovation
Despite rapid advances in editing enzymes and guide RNA design, delivery remains the most pressing bottleneck. Next-generation strategies are targeting this challenge head-on, leveraging nanotechnology and materials science to engineer more efficient and tissue-specific delivery vehicles. LNPs continue to be a workhorse for systemic delivery, but new formulations are being optimized for improved stability, endosomal escape, and targeting to tissues such as the brain and muscle.10
Polymeric nanoparticles and biodegradable scaffolds offer alternative means of encapsulating and delivering RNA-editing payloads, often with enhanced control over release kinetics and reduced immunogenicity. Meanwhile, exosome-based delivery systems are attracting growing attention. These naturally occurring vesicles, which mediate intercellular communication, can be engineered to carry editing components across biological barriers — including the notoriously impermeable blood–brain barrier — and have the added benefit of immune evasion owing to their endogenous origin.11
To further extend the functional life span of RNA therapies in vivo, self-replicating RNA and circular RNA constructs are being explored. These structures resist degradation and can provide more sustained expression of editing machinery from a single dose. Such strategies may enable repeated or long-duration editing in diseases requiring chronic intervention, while reducing the need for high or frequent dosing — an especially important consideration for pediatric and lifelong indications.
Integrating with Broader Therapeutic Modalities
As RNA-editing technology continues to evolve, its role is also expanding beyond monotherapy into combination strategies that could redefine therapeutic paradigms. RNA editing is being explored in conjunction with mRNA vaccines to enhance immune modulation or protein replacement in a controlled, tissue-specific manner. In cell therapy, in situ RNA editing may enable dynamic modulation of immune cell function or safety switches post-administration. Likewise, RNA editing could be layered atop gene therapy constructs to introduce transient control over otherwise permanent edits or to fine-tune expression levels over time.
The potential for combination therapies also underscores the growing importance of companion diagnostics. RNA editing is uniquely suited to precision medicine, as it can be tailored to individual mutations or expression profiles. Biomarker-guided strategies, supported by real-time transcriptomic analysis, could help match patients with the appropriate editing targets and optimize therapeutic outcomes.6
Perhaps most compelling is the expanding scope of diseases that RNA editing may eventually address. While initial applications have focused on rare, monogenic conditions, the field is moving toward more complex indications, including inflammation, neurodegeneration, and cancer. Editing RNA transcripts in these diseases could modulate immune signaling, restore homeostatic pathways, or enhance therapeutic resistance profiles — opening new opportunities to treat diseases not driven by a single genetic mutation but by network-level dysregulation.14
Taken together, these developments suggest that RNA editing is not only here to stay — it is on the cusp of evolving into a fully integrated, multipurpose therapeutic platform capable of addressing a broad spectrum of clinical challenges.
Ethical, Regulatory, and Commercial Landscape
As RNA-editing technologies move from bench to bedside, they bring with them a distinct set of ethical, regulatory, and commercial questions — many of which remain unresolved. Unlike DNA editing, which permanently alters the genome, RNA editing is inherently reversible. This temporality has significant ethical implications, particularly when considering long-term safety and risk. While reversibility can be seen as a safeguard — offering the ability to pause or reverse intervention if adverse effects arise — it also introduces complexities around durability and the need for re-dosing. This tradeoff must be weighed in the context of each disease, especially in pediatric or chronic indications where long-term treatment plans are required.15
From a bioethical perspective, the focus on somatic editing provides a buffer against many of the controversies associated with germline genome editing. RNA editing does not affect inherited DNA, which may position it as a more ethically acceptable approach to modifying biological function. However, as delivery strategies improve and editing becomes more efficient, questions will inevitably arise regarding where to draw the line — especially in contexts where somatic edits might indirectly affect reproductive tissues or long-term epigenetic profiles.
Regulatory frameworks for RNA editing are still taking shape. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have well-established pathways for evaluating gene therapies and RNA-based drugs, but RNA editing exists in a gray area between the two. It is not a permanent gene therapy, nor is it a traditional RNA therapeutic like small interfering RNA (siRNA) or messenger RNA (mRNA). This hybrid identity raises questions about classification, long-term monitoring, and manufacturing standards. Regulators may need to develop new guidelines or adapt existing ones to accommodate the unique features of RNA editing, particularly as first-in-human trials progress.9
Intellectual property (IP) is also a growing battleground in the RNA-editing space. As seen with CRISPR, foundational IP can shape the trajectory of a technology and determine which companies gain early dominance. Several biotech firms have already secured patents on key platform technologies, such as guide RNA design, ADAR recruitment methods, and delivery systems. However, overlap with existing RNA technologies and the potential for broad claims may lead to legal disputes or licensing bottlenecks. Moreover, competition with CRISPR and mRNA platforms — both of which continue to evolve — has created a highly dynamic IP environment where cross-licensing and strategic partnerships are likely to play a central role.13
Despite these uncertainties, investment in RNA editing continues to surge. Venture capital and strategic partnerships have flowed into startups focused on this technology, particularly those showing strong preclinical data or novel delivery platforms. Large pharmaceutical companies are beginning to explore RNA editing either through internal pipeline development or collaborations, seeing it as a promising extension of their nucleic acid therapy portfolios. With more candidates nearing IND status, RNA editing is transitioning from a high-potential niche to a central arena of innovation in molecular medicine.9
As the field matures, resolving ethical, regulatory, and commercial tensions will be critical — not only for ensuring patient safety and public trust but also for unlocking the full therapeutic promise of RNA editing in a competitive and rapidly evolving landscape.
Conclusion – A Therapeutic Platform Matures
RNA editing has arrived at a critical inflection point. Once the province of molecular biology textbooks and arcane enzymology, it is now rapidly transforming into a viable therapeutic modality. The field has moved beyond proof of concept and into a new era marked by programmable tools, early-stage clinical pipelines, and serious investment. What was once appreciated primarily for its biological novelty is now being reimagined as a flexible, precise, and potentially safer alternative to genome editing capable of correcting disease at the transcript level without altering the DNA blueprint itself.7
This trajectory echoes the evolution of CRISPR, which similarly made the leap from bacterial immunity to biomedical mainstay in less than a decade. It also draws clear parallels with the mRNA vaccine revolution, where decades of foundational research suddenly coalesced into real-world impact during the COVID-19 pandemic. RNA editing now stands poised to follow a similar arc, with emerging platforms, delivery vehicles, and regulatory engagement pushing it closer to widespread clinical use.12
But success is not guaranteed. To realize the full potential of RNA editing, the field must continue addressing key challenges: efficient and tissue-specific delivery, editing precision, immune tolerance, and durable yet controllable expression. Just as importantly, regulatory frameworks must evolve to accommodate the unique properties of RNA-editing technologies — balancing innovation with robust standards for safety, efficacy, and reproducibility.8
Ultimately, RNA editing offers more than the ability to correct genetic errors. It provides a means to reprogram biology with unprecedented temporal and spatial precision. By rewriting — not just patching — the transcriptome, RNA editing may enable a new class of medicines that are smarter, safer, and more adaptable to the complexities of human disease.
References
1. Gott, Jonatha M and Ronald B Emeson. “Functions and Mechanisms of RNA Editing.” Annu. Rev. Genet. 34: 499–531 (2000).
2. Nishikura, Kazuko. “Functions and Regulation of RNA Editing by ADAR Deaminases.” Annu. Rev. Biochem. 79: 321–349 (2010).
3. Eisenberg, Eli and Erez Y. Levanon. “A-to-I RNA editing — immune protector and transcriptome diversifier.” Nature. 19: 473–490 (2018).
4. Zhang, Dejiu, et al. “RNA editing enzymes: structure, biological functions and applications.” Cell & Bioscience. 14: 34 (2024).
5. Ruchika, Takahiro Nakamura. “Understanding RNA editing and its use in gene editing.” Gene and Genome Engineering. 3–4: 100021 (2022).
6. Birgaoanu, Maria, Marco Sachse, and Aikaterini Gatsiou. “RNA Editing Therapeutics: Advances, Challenges and Perspectives on Combating Heart Disease.” Cardiovascular Drugs and Therapy. 37: 401–411 (2023).
7. Booth, Brian J, et al. “RNA editing: Expanding the potential of RNA therapeutics.” Mol. Ther. 31: 1533–1549 (2023).
8. Sheridan, Cormac. “Shoot the messenger: RNA editing is here.” Nature Biotechnology. 41:306–308 (2023).
9. Fidler, Ben and Gwendolyn Wu. “RNA editing: emerging from CRISPR’s shadow.” Biopharma Dive. 22 Oct. 2024.
10. McKenzie, Heather. “RNA Editing Hits the Clinic, Fueling New Hope for Rare and Common Diseases.” BioSpace. 24 Feb. 2025.
11. Shah-Neville, Willow. “5 RNA editing companies you should know about.” Labiotech. 28 Jan. 2025.
12. LeMieux, Juliana. “RNA Editing Is Having a Moment.” Genetic Engineering & Biotechnology News. 14 Nov. 2023.
13. Leslie, Mitch. “Edit Kill the Messenger.” Science. 24 Oct. 2024.
14. Liao, Weixue, et al. “The occurrence, characteristics, and adaptation of A-to-I RNA editing in bacteria: A review.” Front. Microbiol. 6 March 2023.
15. Cross, Ryan. “RNA-editing race intensifies as Big Pharma buys in.” c&en. 23 Oct. 2021.