Oral delivery of RNA therapeutics has long been viewed as a scientific improbability due to the instability of RNA and the hostile environment of the gastrointestinal tract. But recent innovations in lipid nanoparticles, polymeric carriers, extracellular vesicles, and even microneedle-based ingestible devices are rapidly reshaping what’s possible. These technologies have demonstrated preclinical success in both local applications, such as treating colitis, and systemic applications, including oral vaccines. Challenges remain in achieving consistent bioavailability, regulatory clarity, and scalable manufacturing, especially for complex nanocarriers. Yet with multiple platforms showing promising translational potential, the first clinical approvals of oral RNA products may be within reach in the coming years.
Why Oral RNA Delivery Matters
Despite the rapid advances in RNA-based therapeutics, delivery remains one of the field’s greatest limiting factors. Today, the overwhelming majority of approved or late-stage RNA drugs rely on parenteral administration, an approach that introduces logistical barriers to repeated dosing, restricts access in low-resource settings, and limits the scope of therapeutic applications. Injectables, while effective in delivering RNA to systemic targets, are often associated with patient discomfort, adherence challenges, and the need for trained personnel or specialized infrastructure.
Oral delivery offers a compelling alternative. A swallowable format could unlock broader access, enable self-administration, and allow RNA therapies to more directly target gastrointestinal (GI) tissues. It also holds the potential to support both local effects, such as the treatment of inflammatory bowel diseases, and systemic responses, as in the case of vaccines and immunotherapies. However, the chemical and physical properties of RNA — its large size, polyanionic charge, and vulnerability to enzymatic degradation — have historically made oral delivery infeasible. The GI tract is an especially hostile environment for nucleic acids, characterized by acidic pH, digestive enzymes, and physical barriers such as mucus and epithelial tight junctions.
Recent breakthroughs are beginning to shift this paradigm. A new generation of delivery platforms ranging from engineered lipid nanoparticles and muco-penetrating poly
mers to food-derived extracellular vesicles and microneedle capsules is demonstrating the feasibility of oral RNA delivery in preclinical models. These technologies are not only overcoming fundamental stability and absorption hurdles but also enabling targeted delivery and translational scalability. As highlighted in recent reviews and experimental studies, these converging innovations are setting the stage for the first generation of orally administered RNA drugs and vaccines to enter the clinic in the years ahead.1–3
Biological and Engineering Hurdles to Gut-Stable RNA
The promise of oral RNA therapeutics remains in tension with the formidable biological and pharmacological barriers that have long constrained their development. Chief among these are the physiological conditions of the GI tract, which are inherently hostile to large, labile biomolecules like RNA. The stomach’s acidic pH and the presence of nucleases throughout the digestive tract drive rapid degradation of unprotected RNA, often within minutes of exposure. These enzymes are evolutionarily designed to break down dietary nucleic acids and pose a significant obstacle to therapeutic stability and integrity.1
Even if RNA molecules survive degradation, they must still traverse the dense mucus layer that lines the epithelium and then cross a tightly regulated cellular barrier. The intestinal epithelium is highly selective, limiting the translocation of macromolecules via tight junctions and low rates of endocytosis. Furthermore, RNA’s polyanionic nature and large molecular weight hinder passive diffusion and make active transport mechanisms inefficient without the aid of specialized carriers.1,4
Another layer of complexity arises from the immune system. While RNA-based therapeutics can be designed to minimize innate immune activation, oral delivery increases the risk of triggering unintended inflammatory responses, particularly in inflamed or compromised GI tissue. Pattern recognition receptors in gut-associated lymphoid tissue can detect foreign RNA, potentially leading to off-target inflammation or tolerogenic effects that reduce therapeutic efficacy.4
From a pharmacological perspective, bioavailability remains a major concern. Even with protective formulations, only a small fraction of orally delivered RNA typically reaches its intended site of action. This low efficiency demands larger doses, which can be challenging to encapsulate in a single administration and may introduce issues with reproducibility and scale. Moreover, different therapeutic applications require distinct biodistribution profiles — some targeting local GI tissues, others aiming for systemic delivery — further complicating design constraints.5
These cumulative challenges underscore why oral RNA delivery has remained largely aspirational until recently, but they also point directly to the functional targets that today’s most promising technologies are designed to overcome.
Targeting Inflammation: Local RNA Therapeutics in the Gut
Among the most promising initial applications of oral RNA therapeutics is local delivery to the gastrointestinal tract, particularly for inflammatory conditions, such as ulcerative colitis and Crohn’s disease. Unlike systemically administered RNA drugs, which must navigate a range of pharmacokinetic barriers to reach distant tissues, locally delivered RNA can act directly at the site of disease, significantly reducing the requirements for absorption, distribution, and systemic exposure. This approach also allows for lower effective doses, simpler formulation demands, and decreased risk of off-target effects.
One of the most advanced preclinical strategies in this area centers on the use of interleukin-22 (IL-22) mRNA to stimulate epithelial repair and modulate inflammation in colitis models. Several groups have demonstrated that oral delivery of IL-22 mRNA can significantly ameliorate disease severity in mice by promoting mucosal healing and suppressing pro-inflammatory cytokines. In particular, a novel ginger-derived nanoparticle-like lipid nanoparticle (LNP) formulation has shown high selectivity for inflamed colonic tissue, leveraging the unique lipid profile of edible plants to enhance delivery and reduce immune activation.4
A second, complementary approach utilizes engineered capsule systems to deliver intact mRNA to the small intestine. The RNACap platform, for example, combines enteric protection with lipid nanoparticle encapsulation to enable the oral administration of liquid mRNA payloads. In preclinical models, RNACap successfully delivered IL-22 mRNA to the intestinal tract and produced therapeutic effects comparable to injectables, without triggering systemic toxicity or degradation.2 These findings are reinforced by studies using modified lipid nanoparticles designed for bile salt and enzyme resistance, which have achieved similar results in inflamed gut environments.6
Targeting local GI tissues represents a logical and achievable first step in the clinical translation of oral RNA therapeutics. It aligns the strengths of emerging delivery technologies with a well-defined therapeutic need, while avoiding many of the systemic barriers that complicate broader applications. As delivery platforms continue to mature, this use case may serve as a foundational proof of concept for more complex and ambitious RNA treatments.
Strategies for Protection and Penetration
Effective oral RNA delivery demands a multifaceted approach to overcome the numerous physical and biochemical obstacles of the gastrointestinal tract. Central to these efforts is the development of protective and penetrative delivery systems that can shield RNA molecules from degradation, navigate biological barriers, and facilitate uptake at target sites. A wide range of encapsulation and formulation strategies are now being explored to meet these challenges.
Encapsulation is one of the most widely used methods for protecting RNA during transit through the stomach and upper intestines. Enteric coatings formulated to remain intact in acidic environments but dissolve at the higher pH of the small intestine are frequently employed in capsule-based systems to prevent premature release. The RNACap platform, for instance, uses a layered enteric capsule to deliver intact liquid mRNA directly to the intestine.2 Other approaches rely on gastroresistant vesicles, such as lyophilized extracellular vesicles stabilized within protective matrices, which have demonstrated resilience to gastric conditions and the ability to preserve mRNA payloads through digestion.7,8
Beyond encapsulation, the design of the nanoparticles themselves plays a critical role in stability, targeting, and intracellular delivery. LNPs remain a foundational platform in RNA delivery, and their composition can be tuned for oral applications. Ionizable lipids facilitate endosomal escape once inside target cells, while cationic and neutral lipids help balance charge interactions and improve compatibility with mucus and cellular membranes. Recent formulations optimized for oral use, such as those described in the OrD LNP system, have shown enhanced resistance to bile salts, intestinal enzymes, and mucus entrapment.6 Other LNP systems have incorporated mucus-penetrating layers to improve delivery to immune-inductive sites like Peyer’s patches.9
Polymeric nanoparticles also offer a versatile alternative. Materials, such as poly(β-amino esters) (PBAEs) and polyethylene glycol (PEG) derivatives, have been used to form stable complexes with RNA, enabling controlled release, immunostimulatory activity, and improved tissue penetration. These systems can be lyophilized for storage and rehydrated upon ingestion, offering a practical advantage for global distribution and shelf stability.5,10
Extracellular vesicles (EVs) derived from food sources, such as citrus and ginger, present another intriguing strategy. These vesicles naturally contain lipids and surface proteins that aid in mucosal transport and cellular uptake and can be loaded with synthetic mRNA for delivery. Their biocompatibility and scalability make them especially appealing for vaccine applications or therapies requiring regular dosing.7,8
To further enhance uptake, surface modifications are increasingly being employed to improve translocation across the intestinal epithelium. Cell-penetrating peptides have shown promise in facilitating endocytosis and bypassing tight junctions, particularly when combined with liposomal carriers.11 Other systems incorporate mucus-penetrating coatings that prevent nanoparticle aggregation and enable deeper diffusion through the mucosal layer.9
Taken together, these innovations in formulation and particle design are transforming oral RNA delivery from a theoretical challenge into a practical engineering problem that is rapidly yielding workable solutions.
Active Delivery Systems: Beyond Passive Diffusion
While most oral RNA delivery strategies rely on shielding and facilitating absorption through biological barriers, some approaches are circumventing these challenges altogether through mechanical innovation. One of the most advanced examples is the development of capsule-based microinjection systems designed to actively deliver RNA payloads directly into the tissue lining of the gastrointestinal tract.
This concept has been realized in a swallowable capsule developed at the Massachusetts Institute of Technology that uses a microneedle injector to deliver mRNA nanoparticles into the stomach lining. The capsule is engineered to orient itself correctly after ingestion using asymmetric geometry and to activate only once it reaches the appropriate pH environment of the stomach. Upon actuation, a microneedle-like mechanism injects the encapsulated mRNA, formulated with branched PBAE polymers, into the gastric mucosa, bypassing the need for transport across the epithelial barrier.3,12
This active delivery approach offers several advantages over traditional diffusion-based strategies. Most notably, it avoids exposure of the RNA payload to the acidic and enzymatically harsh environment of the stomach lumen, thereby preserving its integrity and bioactivity. By delivering directly to tissue, the system also improves the potential for systemic uptake, overcoming the limitations of low intestinal permeability. In preclinical studies, capsules delivered up to 150 micrograms of mRNA per dose in pigs — a payload comparable to those used in current mRNA vaccines — and successfully induced expression of the encoded protein in gastric tissue.12
While still early in development, this class of active devices expands the possibilities for oral RNA therapeutics beyond the confines of local GI applications. It introduces a paradigm where systemic delivery may be achieved not by overcoming natural barriers but by bypassing them through precisely engineered actuation and targeting. As these technologies mature, they could open new frontiers for RNA-based treatments requiring high-dose systemic exposure in a patient-friendly oral format.
Oral RNA Vaccines: Mucosal and Systemic Immunity
Oral delivery is particularly well-suited to RNA vaccines, which aim not only to generate systemic immunity but also to engage mucosal defenses at the site of pathogen entry. Unlike injectable vaccines that typically stimulate circulating antibody and T cell responses, oral RNA vaccines have the potential to elicit both systemic immunity, through IgG and cytotoxic T-cell activation, and mucosal immunity, primarily through secretory IgA. This dual protection is especially important for respiratory and enteric viruses that exploit mucosal surfaces as initial points of infection.
Preclinical studies have demonstrated the feasibility of this approach using a variety of oral RNA vaccine platforms. One promising strategy involves the use of plant-derived EVs as carriers. These naturally occurring nanoparticles, isolated from edible sources, such as citrus fruits, can be loaded with mRNA encoding viral antigens and administered by oral gavage. Once encapsulated in gastroresistant formulations and lyophilized for stability, these EV-based vaccines have induced robust mucosal and systemic immune responses in rodent models, including both IgA secretion and serum IgG against SARS-CoV-2 spike protein.7,8
Other platforms are leveraging synthetic materials to achieve similar outcomes. PBAE-based nanoparticles, formulated for oral stability and targeted delivery to intestinal immune inductive sites, have been shown to generate strong CD8+ T cell responses and high levels of antigen-specific antibodies after oral administration.5 Hybrid systems that combine polymers and lipids have also demonstrated success in overcoming gastrointestinal barriers, enhancing cellular uptake, and promoting dendritic cell activation, which is critical for initiating adaptive immunity.10
Beyond their immunological advantages, oral RNA vaccines offer clear logistical benefits. Their lyophilized formulations eliminate cold-chain requirements, enabling room-temperature storage and transport. Oral administration also removes the need for syringes or trained healthcare personnel, reducing costs and increasing accessibility in low- and middle-income countries (LMICs). These attributes position oral RNA vaccines as powerful tools for global immunization efforts, especially in settings where conventional delivery systems fall short.
As more preclinical platforms demonstrate efficacy, the first-in-human studies for oral RNA vaccines may not be far behind. If successful, they could significantly expand the reach of RNA vaccine technology, not only for emerging infectious diseases but also for cancer immunotherapy and therapeutic vaccination against chronic infections.
From Bench to Bottle: The Road to Clinical-Grade Oral RNA
Translating oral RNA therapeutics from preclinical promise to clinical practice will require overcoming not only scientific challenges but also regulatory and manufacturing hurdles. As with all novel drug modalities, success will depend on demonstrating reproducible quality, safety, and efficacy under conditions that meet current good manufacturing practices (GMP). For oral RNA formulations, this path is complicated by the diversity and complexity of the delivery systems involved.
Stability and manufacturability are immediate concerns. Lyophilization, which enables room-temperature storage and long-term shelf life, has emerged as a critical enabling technology, particularly for RNA vaccines and therapies intended for global distribution. Several promising platforms have shown that lyophilized RNA formulations can retain biological activity after rehydration and withstand gastrointestinal transit, including polymeric systems and EV-based carriers.5,8 However, consistency in particle size, RNA loading efficiency, and batch-to-batch reproducibility remain key quality attributes that must be carefully validated, especially when using biologically derived materials, such as plant-based EVs.
Scaling these systems poses another challenge. Many nanoparticle platforms — whether lipid-based, polymeric, or vesicular — require specialized production methods that may not yet be standardized at industrial scale. Ensuring compatibility with GMP processes and achieving sufficient yield, purity, and reproducibility without compromising function are essential for clinical advancement. These concerns are especially relevant for active delivery devices like microneedle capsules, which must integrate mechanical, chemical, and biological components in a single unit.12
Regulatory assessment of oral RNA therapeutics will also depend on the development of appropriate models for evaluating oral bioavailability and pharmacokinetics. Traditional absorption metrics may not apply to localized therapies, and novel endpoints will be needed to capture tissue-specific expression, immune responses, or therapeutic impact at the mucosal level. As these products challenge conventional classification, touching on overlapping drug, biologic, and device frameworks, regulatory clarity will be critical to guiding development and investment.
Looking ahead, several innovations could help bridge the gap from lab to clinic. The incorporation of oral adjuvants or protective enzyme inhibitors may boost efficacy, while platform technologies that allow interchangeable payloads could streamline regulatory review. As the field matures, the first-in-human trials of oral RNA therapeutics may emerge from those programs that best align formulation performance with manufacturing feasibility and regulatory expectations.1,6 If successful, these early entrants will set the precedent for a new generation of RNA-based treatments that are not only potent and precise but also patient-friendly and globally accessible.
The Tipping Point: Oral RNA’s Move Toward Clinical Reality
The last few years have brought remarkable progress in the field of oral RNA therapeutics, transforming what was once considered a near-impossible route of administration into an increasingly tangible goal. Targeted delivery to the gastrointestinal tract has already demonstrated therapeutic relevance in preclinical models of colitis, while oral RNA vaccines have shown the ability to generate both mucosal and systemic immune responses. Meanwhile, active delivery technologies like microneedle capsules have proven that even systemic RNA exposure can be achieved via the oral route under the right conditions.2,12
Nonetheless, key barriers remain. Achieving consistent systemic bioavailability for broad therapeutic indications continues to pose a significant technical and biological challenge. Manufacturing complexities, especially for biologically derived carriers and multifunctional devices, must be resolved to meet regulatory and commercial standards. And as novel platforms push the boundaries of existing classifications, clear and supportive regulatory frameworks will be essential for clinical translation.1
Despite these hurdles, the trajectory is clear. With continued innovation and sustained investment, the first clinical approvals of oral RNA therapies are likely within reach over the next five to 10 years, particularly for localized GI diseases, prophylactic vaccines, and other indications where oral administration confers a distinct advantage. Whether enabled by lipid nanoparticles, polymeric systems, extracellular vesicles, or ingestible devices, oral RNA delivery is emerging not just as a technical achievement, but as a future standard in how gene-based medicines are administered.
References
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