Most mRNA Design Sucks (And Most Vendors Won't Tell You)

Most sequences being used in mRNA therapeutic development today are fundamentally flawed. And the worst part? Many researchers have no idea.

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The Uncomfortable Truth

While you're busy optimizing formulations, tweaking assays, and meticulously planning pre-clinical studies, you may be working with mRNA that's hobbling your chances of success from the start. Those disappointing expression levels? That unexpected immunogenicity? The frustrating batch-to-batch variability? They're not random bad luck—they're predictable consequences of poor sequence design.

Here's what the standard vendors won't tell you: their "optimization" services aren't optimizing for your success. They're optimizing for their manufacturing convenience.

When we analyzed sequences from established vendors, we found a consistent pattern. Their optimization tools primarily adjust GC content and eliminate features that make synthesis challenging. Oftentimes, these changes are not disclosed to the end user. In a world in which the best sequence is often a highly complex one, this is troubling. What the ‘optimization’ tools don't address: targeted codon usage, translation kinetics, protein folding dynamics, or RNA stability determinants—you know, the factors that actually matter for therapeutic performance.

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The Data Doesn't Lie

In one particularly telling case, we received material from a partner that had been "optimized" by a leading vendor. Upon inspection, we determined that their requested UTRs were swapped out (unbeknownst to them) and the total integrity was only 54%. After Terrain applied actual design principles that consider biological context, not just manufacturing ease, we delivered the CORRECT sequence at over 90% integrity.

This isn't an isolated incident. We've seen similar results across multiple therapeutic classes:

• Improving integrities from 60% to 95%
• Achieving 3x higher expression after Terrain’s design services
• Increasing resistance to hydrolysis by several fold

What's most alarming? The companies often have no way to know what they're missing. They accept 50-60% integrity as "normal" because that's what they've always gotten. They ‘design’ around poor expression by elevating the dose. They attribute immunogenicity to "the nature of mRNA" rather than fixable design flaws.

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Standard vendors make their money on their volume, not your performance.

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The Industry's Dirty Secret

Here's why this problem persists: the economics of the mainstream mRNA industry don't reward quality. Standard vendors make their money on their volume, not your performance. Their business model incentivizes them to process your sequence as quickly and cheaply as possible, not to ensure it actually works in your biological system.

Most offer free optimization services that apply the same generic algorithm to everything from membrane proteins to secreted enzymes to liver-targeted gene editors—as if biological context doesn't matter.

And when your studies show disappointing results? They'll happily sell you more material to try again, never addressing the fundamental design issues that caused the problem.

At Terrain, we've taken a fundamentally different approach: we listen to you to understand the biology that your medicine addresses; we use the latest advancements and computational methods to explore the relevant sequence space; we aim to give you the right mRNA as fast as possible to get your project to the clinic.

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Breaking the Cycle

The first step toward better outcomes is recognizing that there is a problem. If you're working with mRNA and any of these sound familiar:

• Inconsistent expression levels between batches
• Lower-than-expected protein production
• Expression that drops off rapidly after delivery
• Unexplained immunogenicity
• Need for unusually high doses to achieve effects

...then your sequence design is likely contributing to these issues.

Real optimization doesn't just tweak GC content and call it a day. It considers the specific biological context of your therapeutic, the characteristics of your target protein, the tissue-specific environment where expression occurs, and dozens of other parameters that affect performance.

The difference between merely functional mRNA and truly optimized mRNA isn't marginal—it's transformative. The question is: are you willing to acknowledge what’s missing?

Your science deserves better mRNA. Talk with me today.