Scalable and sustainable enzyme-enabled manufacturing for the next wave of RNA therapeutics

Driven by continued innovation and clinical advancement, the global RNA therapeutics market is projected to reach $25 billion by 2030 [1], offering precise treatment options across a growing spectrum of diseases.

As the field progresses toward broader clinical adoption and commercial scale, manufacturing efficiency has emerged as a defining bottleneck. While innovation in RNA design continues at speed, existing production technologies are increasingly constrained by limitations in scale, capacity and sustainability.

To maintain development momentum and ensure reliable commercial supply, RNA manufacturing platforms must move beyond approaches that rely on physically constrained assets, solvent-intensive workflows and incremental scale-up strategies. Addressing these challenges is critical for enabling the next generation of RNA-based medicines.

The limitations of SPOS

Solid-phase oligonucleotide synthesis (SPOS) remains the standard approach for manufacturing RNA therapeutics, valued for its precision and reliability in assembling short sequences.

However, when it comes to the efficient large-scale manufacturing of RNA-based medicines, SPOS presents structural limitations. This includes challenges associated with:

• Batch size limitationsPhysical constraints arising from oligonucleotide immobilization on solid support limit batch output to roughly 5–10 kg. Consequently, commercial production is typically achieved through parallelization of synthesis columns rather than true scale-up.
• Product integrityRepeated exposure to aggressive reagents and cleavage conditions introduces impurities. While necessary, subsequent purification steps result in product loss and increased process mass intensity (PMI).
• Operational hazards
  
  The requirement for large volumes of flammable, hazardous solvents (such as acetonitrile, dichloromethane or toluene) demands specialized engineering controls. Facilities require extensive waste-management systems and explosion-proof architecture, significantly increasing CapEx and OpEx.
• Sustainability concernsThe current SPOS workflow generates substantial chemical waste, posing worker safety challenges and conflicting with green chemistry and ESG standards.

A more scalable, sustainable approach to RNA synthesis

Enzyme-enabled oligonucleotide synthesis is widely seen as a scalable, sustainable, flexible alternative to SPOS. Combining nucleic acid synthesis with machine-learning-driven protein engineering offers a scalable breakthrough for RNA manufacturing. This approach utilizes engineered polymerases and ligases as robust biocatalysts, optimized to assemble oligonucleotides with high stability and tolerance for complex therapeutic modifications.

Unlike solid-phase methods, these enzymatic reactions occur in solution, eliminating physical batch constraints. Operating in mild, water-based conditions removes the need for hazardous solvents and minimizes chemical by-products. This process purity simplifies downstream processing and boosts yields, providing a cleaner, faster and more efficient path to large-scale production of next-generation RNA medicines.

Next-generation RNA manufacturing

Ligation-based approaches are already reshaping the landscape of RNA production, serving as a vital bridge between traditional chemical synthesis and a fully enzymatic future. Currently utilized at multi-kilogram scales for clinical applications, this approach offers distinct advantages:

• Modular flexibility
  dsRNA ligases stitch together short RNA fragments to create full-length therapeutic oligonucleotides. This modularity de-risks the supply chain, allowing manufacturers to source fragments via either chemical or enzymatic means.
• Purity
  By assembling shorter fragments, developers avoid the cumulative yield loss and quality degradation typical of long, stepwise SPOS cycles. This minimizes downstream purification and allows for better management of complex sequences and structural modifications.
• Regulatory confidence
  Because ligase-based workflows have already been proven in clinical-scale manufacturing, they offer a familiar and credible pathway for regulators, thereby accelerating the broader industry adoption of enzymatic tools.

Adapting manufacturing for the next phase of RNA therapeutics

As RNA therapeutics continue to expand in scope and complexity, manufacturing technologies must evolve just as quickly.

Enzyme-enabled synthesis offers a more adaptable and sustainable framework, capable of supporting the next generation of RNA medicines through modularity, scalability and precision. By adopting enzyme-driven approaches now, developers can build manufacturing systems ready for the growing diversity of RNA modalities.

To explore how enzymatic synthesis is shaping a more flexible future for RNA therapeutics, read the full article by Stefan Lutz, PhD, Chief Scientific Officer.

The Medicine Maker | Building the Future of RNA Manufacturing

References

1. Allied Market Research. (April 2025). RNA Based Therapeutics Market by Type, Application, and End User: Global Opportunity Analysis and Industry Forecast, 2021–2030. https://www.alliedmarketresearch.com/RNA-based-therapeutics-market