RNA that lasts longer and lands exactly where it should

RNA therapeutics have progressed rapidly over the past decade, yet two fundamental challenges continue to limit the field: how long therapeutic RNA can express a protein in the body and which cells receive that message. These constraints have shaped what RNA medicines can achieve, from the transient expression needed in vaccines to the difficulty of addressing chronic or complex diseases where sustained and cell specific delivery is essential.

For Dr Ewen Cameron, Head of Platform at Sail Biomedicines and an Operating Partner at Flagship Pioneering, these limitations signal an opportunity. His team is developing a platform that brings together two technologies designed to address long-standing bottlenecks: Endless RNA (eRNA), an engineered circular form of RNA that enables durable, tunable protein expression and targeted nanoparticles (TNPs) capable of delivering that message to defined cell types in the body.

The aim is to build programmable medicines that behave more like software: targeted, adaptable and controllable, without genomic integration.

Building platforms for programmable medicines

Cameron describes himself as a molecular microbiologist who has spent his career developing programmable medicine platforms. At Sail he leads a team focused on eRNA therapeutics and targeted delivery systems designed to work together to solve two long-standing problems in RNA medicine: how long a cell expresses a therapeutic protein and which cells receive the message.

“At Sail Biomedicines, I lead the platform team that is developing both Endless RNA (eRNA) therapeutics, an engineered circular form of RNA that supports durable protein expression and targeted nanoparticles (TNPs) that enable highly efficient delivery to specific cell types in the body.”

To understand why this matters, it helps to consider the limitations of current RNA technologies. Linear mRNA revolutionised the field by enabling cells to produce therapeutic proteins from a temporary genetic message. However, its short lifespan is an inherent feature of how cells regulate their own biology. Cells rapidly degrade linear RNA to adapt to changing conditions, which is helpful in nature but challenging for drug developers who need sustained protein expression. Circular RNA offers a way to change this profile because its closed structure is naturally more resistant to degradation.

Why circular RNA matters

Circular RNA is naturally more resistant to degradation because it lacks free 5’ and 3’ ends. The closed loop structure protects the molecule from cellular mechanisms that normally deadenylate, decap and degrade linear transcripts. As Cameron explains, this structural stability is central to Sail’s approach.

“Circular RNA solves this structural problem; the closed loop resists exonuclease degradation and enables more durable protein production.”

Sail’s vision has been to engineer this biology into a modality designed for therapeutic use. eRNA constructs draw from the natural form but incorporate features that enable efficient translation. This supports smoother, more extended expression windows than conventional mRNA, which typically produces a rapid burst of protein followed by a steep decline within a day or two.

In preclinical studies, eRNA constructs support multi-day expression with reduced peak-to-trough variability. This is important because a high peak can contribute to toxicity, while a rapid drop can limit effectiveness. Sustained, predictable expression gives developers a way to match pharmacology to disease biology.

Overcoming the burst-and-fade limitations of mRNA

The difference is not only structural but functional.

Linear mRNA begins translating immediately upon entering the cell, producing fast but short-lived expression. This is ideal for vaccines but insufficient for applications that need prolonged protein production.

eRNA’s increased stability supports multi-day expression in preclinical models, with reduced peak-to-trough variability compared to the burst-and-fade profile typical of linear mRNA.

“eRNA’s increased stability supports multi-day expression in preclinical models, with reduced peak-to-trough variability compared to the burst-and-fade profile typical of linear mRNA.”

Because Sail has generated data from libraries of hundreds of thousands of eRNA variants, the team can now use AI-informed design to tune expression characteristics. This includes predicting stability, translation efficiency and expression kinetics based on sequence and structure.

The result is an RNA modality that can be tailored to different therapeutic needs, from transient expression for cell programming to sustained expression for chronic conditions.

Early therapeutic opportunities

The first areas where Sail is applying this technology are autoimmune disease and vaccines.

“By delivering eRNA constructs encoding a CD19 CAR into a patient’s own T cells via TNPs, we can transiently reprogram T cells in the body.”

By delivering eRNA constructs encoding a CD19 CAR into a patient’s own T cells via TNPs, we can transiently reprogram T cells in the body.

In preclinical models, this approach achieved deep depletion of B cells across blood, lymph nodes and bone marrow progenitors. The outcome resembles the immune reset observed with autologous CAR-T therapies but without the complexity of harvesting, engineering and reinfusing cells. This suggests a possible path toward off-the-shelf in vivo cell therapies.

A second application is in vaccination. eRNA’s stability and expression duration can support stronger, more durable immune responses than protein or first-generation mRNA vaccines. Sail’s malaria studies have shown encouraging immunogenicity, with antibody titres substantially higher than protein comparators and maintained for extended periods.

Delivery as a design feature

Durability is one part of the equation; the other is delivery. Sail’s TNP platform is designed to deliver eRNA constructs to specific cells while avoiding off-target tissues. The team has built a large library of biodegradable ionisable lipids and selective targeting ligands, informed by AI models trained on extensive in vivo biodistribution datasets.

Cameron notes that this combination of chemistry and machine learning allows precise delivery to circulating and tissue resident immune cells.

“Our targeted nanoparticles functionalised with ligands against CD4 and CD8 T cells achieve 60–80 percent transfection of T cells in non-human primates, with minimal hepatocyte expression.”

Because the nanoparticle system is modular, swapping targeting ligands allows redirection to other immune cells with similar selectivity. Delivery becomes a tunable variable rather than a fixed constraint.

Three system-level challenges

Despite the progress, Cameron is clear that realising the full potential of eRNA medicines requires solving three integrated challenges.

“We’re solving three system-level challenges: 1) precision targeting at scale, 2) high performance eRNA design and 3) manufacturing, as a single integrated problem.”

These include:

• Precision targeting at scale, enabling selective delivery to circulating immune cells and tissue-resident cells across compartments such as liver, spleen and bone marrow.
• High performance eRNA design, using AI-guided sequence-to-structure modelling.
• Manufacturability and quality, ensuring consistent, high-purity eRNA-TNP products suitable for clinical use.

A key differentiator for Sail is that these elements are not optimised independently. RNA structure, nanoparticle chemistry and dosing strategies are co-designed against disease biology. High-throughput data generation and semi-automated testing underpin this approach.

Beyond vaccines: toward chronic and complex diseases

Durable, programmable expression enables applications beyond vaccination. With targeted nanoparticles, eRNA constructs can support in vivo cell programming and controlled production of secreted, membrane or intracellular proteins.

“RNA can become a programmable medicine class for chronic and complex indications in addition to vaccines.”

The lead programme aims to achieve deep immune reset in autoimmune disease with an off-the-shelf product that could be administered in outpatient settings. This contrasts sharply with the multi-week process required for current ex vivo CAR-T therapies.

Bringing eRNA medicines to the clinic

Sail is now progressing from platform development toward clinical translation.

“Data presented at ASGCT this year support advancing our vanguard in vivo CAR-T program in autoimmune disease into IND-enabling studies.”

The company’s vaccine efforts include a malaria program funded by the Gates Foundation. Following optimization of the eRNA design, further steps towards candidate development may include formulation selection, non-human primate immunogenicity studies, manufacturing scale-up and safety evaluation.

The broader goal is to build a pipeline of RNA medicines that use the same foundational tools: programmable eRNA constructs and targeted nanoparticle delivery.