RNAi vs. mRNA: Two Therapies, Two CDMO Strategies

By Louis Garguilo, Chief Editor, Outsourced Pharma

The biotech industry is often described in grand dichotomies such as innovator vs. generic, small molecule vs. large molecule, or clinical vs. commercial.

These and other differentiators influence development and manufacturing, the selection of CDMOs, and outsourcing strategies.

My colleague at Advancing RNA, Chief Editor Anna Rose Welch, recently reminded me there are other, more nuanced pairings, and said this one warrants a look: mRNA vs. RNAi.

Yes, both are built on RNA-based platforms, and seek intracellular action. Both have navigated (with some difficulties) to FDA approvals.

As most readers know, the “m” in mRNA is for “messenger,” fundamentally applied to express proteins; and the “i” in RNA is for “interference,” to silence disease-causing genes.

When it comes to development and manufacturing trajectories, and CDMO partnerships, mRNA and RNAi can send sponsors on quite different arcs. Recognizing this is critical for sponsors and CDMOs alike.  

Our treatment here of this theme can broadly assist readers working in any modalities — or sub-categories — as you think through your particular programs and outsourcing needs.

Enzymes vs. Chemistry At CDMOs

For CDMOs, the foundational question should always be:

What exactly are we being asked to produce?

For mRNA, that answer predominantly lies in biologic-like processes: in vitro transcription (IVT) from DNA templates using certain enzymes; post-transcriptional capping; and purification steps to remove double-stranded RNA contaminants – wrapped in the delicate handling required of long, often unstable strands of nucleic acid.

Sponsors should be careful. Even those CDMOs previously experienced in biologics may find this new RNA mountain difficult to climb.

RNAi, most commonly in the form of synthetic siRNA is grounded in solid-phase chemical synthesis.

This is a platform well-known to CDMOs with oligonucleotide capabilities, and benefits from decades of refinement and scalability, drawing from antisense and aptamer development. The result is a more mature, even commoditized process.

Immediately, then, we see how CDMO selection should be amply discriminatory.

Word on the street is many mRNA players continue to search for CDMOs who’ve invested in IVT suites, specialized LNP formulation systems, and the analytical methods required to ensure final product is both potent and pure.

Meanwhile, RNAi players more happily find themselves picking from a broader array of providers, particularly those with oligo pedigree.

Delivery and Formulation Implications

Both mRNA and RNAi therapies require advanced delivery vehicles, most prominently lipid nanoparticles (LNPs).

However, the payloads and formulation sensitivities differ.

mRNA molecules are longer, more structurally complex, and more immunogenic. Their encapsulation into LNPs requires precise ratios, end-to-end sterility, and preservation of RNA integrity—tasks not easily transferred across production sites or to CDMOs.

RNAi molecules, especially GalNAc-conjugated siRNAs, have carved out a more straightforward delivery mechanism—leveraging receptor-mediated uptake without LNPs. But even for those that do use LNPs, their smaller oligo size allows for a broader manufacturing window.

It follows that for mRNA sponsors, the CDMO is often a full development partner, guiding through scale-up, optimization, and regulatory readiness.

For RNAi sponsors, the CDMO might be considered more as a technical resource, called upon to reliably deliver batches from an established playbook.

That distinction can influence pricing models, any risk-sharing structures and other contracting negotiations, and project timelines.

CDMOs and sponsors should probe the differing calculations in these relationships – and the mutual flexibilities needed for optimal outcomes.

Two Paths To Regulatory Readiness

We can still assert that mRNA is a comparatively novel therapy.

COVID-19 vaccines may have fast-tracked acceptance, but regulators continue to scrutinize mRNA therapeutics for their impurity profiles, stability data, and combination product complexities, and potential adverse affects.

That puts an additional burden on CDMOs. Not only must they meet standard GMP compliance, but also co-develop reliable analytical methods, support preclinical toxicology batches, and maintain flexibility as the regulatory landscape changes.

RNAi, on the other hand, has become a more familiar entity to health authorities. With approved therapies like ONPATTRO, GIVLAARI, and LEQVIO, the path from IND to approval has been established. CDMOs can lean on experience, existing platforms, and fewer regulatory surprises.

For sponsors, that means on the one side, less need for regulatory hand-holding in RNAi outsourcing, and on the other, more partnership-by-design for mRNA programs.

In fact, it’s reported that some CDMOs are segmenting their business units accordingly—creating separate innovation groups for mRNA, while routing RNAi work through legacy oligo divisions.

Responding On Both Sides

Drawing on the above – and what we know about the fundamentals of outsourcing – we can document some final comparisons.

For the mRNA folks, early CDMO engagement is recommended, and could be beneficial from even the research stage.

CDMO selection must account for co-development capability, tech transfer complexity, and custom formulation know-how. And look for long-term partnerships where possible; switching vendors can add months of revalidation and other lost time.

RNAi sponsors get the luxury to and should shop around for the best pricing, earliest capacity, most appropriate delivery models, and place a premium on experience in oligo synthesis and conjugation chemistry.

And don’t waste time in that due diligence process. Remember that once contracts are signed with CDMOs, relatively shorter-duration development timelines mean heightened pressures to hit the ground running for scale ups and up-phasing.

Regarding deal structures:

mRNA sponsors pursue multi-year, multi-phase engagements with leading-edge CDMOs;

RNAi players may choose a modular outsourcing strategy, switching vendors as programs progress.

On the CDMO side, mRNA customers are enticed with the building of dedicated IVT suites, custom LNP fill/finish lines, and RNA-specific analytical labs.

Other CDMOs are doubling down on oligos, seeing RNAi (and the adjacent antisense space) as a stable, scalable growth area with high repeat business and expanding indications.

And (of course!) there are CDMOs looking to straddle both. Besides the obvious business reasoning, CDMOs may be thinking we'll experience a period of convergence, where flexible platforms will serve a variety of therapies – mRNA, RNAi, CRISPR, antisense, and whatever else is out there or comes next.

The RNA revolution has been exciting, if not a bit bumpy, and it is far from over.

The most efficient and enlightened matching up of sponsors and CDMOs will help smooth the road ahead. Select your RNA program, and then your CDMOs, wisely.

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The editor would also like to thank Jon Cooper, VP, RNA Sciences and Analytical Development, Aldevron, for his review before publication.