Two "Hot Takes" On mRNA Delivery

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

There are a lot of questions we must answer in the encoding RNA space to ensure long-term success. But at the end of the day, to have a mature and broadly applicable mRNA therapeutics sector, we need to be able to deliver our products to the appropriate organs/cells. No one in the RNA space is disputing this truth. In fact, ask anyone to identify a limiting factor for the RNA therapeutics space in the long-term, and “delivery” is likely in their list of top 3 concerns (if not #1 itself).

But despite the industry’s anxiety about delivery, there’s been strikingly little diversity in the mRNA delivery space thus far. LNPs have been the delivery vehicle of choice for a majority — upwards of 80 percent — of (disclosed) mRNA products today. Of course, there are some significant reasons for LNPs’ current gravitational pull — the fact that they’ve been “derisked” from a regulatory standpoint being a pretty good one. It’s also not lost on any of us that funding is not what it used to be. Having the time, talent, flexibility, funds, and risk tolerance to invest in and help scientifically advance more than one delivery vehicle (or start out with a less mature technology) is a luxury to which many of us are not currently entitled. I’d also be selling the industry short if I didn’t acknowledge that there is a lot of groundbreaking work being done in academia and private industry to better understand, design, and manufacture more “well-rounded” LNPs.

All that said, placing most of our (non-vaccine) therapeutic product bets on LNP delivery technology alone is one of my biggest concerns about the mRNA space today — especially as we strive to build a diverse, broadly applicable therapeutics industry. That’s why I was excited to see there was a focus on the topic of nonviral delivery — namely polymer and exosome delivery — during the BioPhorum ATMP Member Event this spring. First and foremost, these discussions served as a friendly reminder that there is a wild (and wide!) nonviral delivery world out there for us to explore more thoroughly. However, as we were also reminded, our conversations about the benefits and challenges of nonviral delivery mechanisms are easily prone to both positive & negative generalities, which can hinder our scientific progress and, in some cases, diminish our appetite for exploring novel non-LNP delivery areas.

As I argued in a previous “Hot Take,” “the devil is in the details” when it comes to developing both our drug substances and our drug products. We need to get to the point where we have more details and knowledge about alternative methods of delivery (beyond LNPs) so we can make educated decisions on the best path forward for delivering our products. And, as I was reminded during the BioPhorum event, there is actually great value in gathering less-than rosy data about a specific delivery mechanism — especially in these early days.

Hot Take #3: To Unlock New mRNA Delivery Mechanisms, We Need Fewer Generalities

I’ve argued before that, in the mRNA-LNP space, we tend to gloss over the many formidable challenges associated with LNP development in favor of a narrative that the technology is much better understood and more mature than it really is today. Likewise, as several conversations during the BioPhorum event revealed, we do the same thing with less mature delivery technologies, like polymers and exosomes. In particular, we tend to paint these heterogenous technologies with too broad a brush today.

Take extracellular vesicles (EVs) and exosomes, for example. As one speaker explained during their presentation, while these two terms are often used interchangeably today, exosomes are only one specific subpopulation of EV — and cells (in humans, plants, and bacteria) produce many different types of EVs. To be clear, not all EVs/EV subpopulations are being explored in therapeutic applications; but this presentation was a good reminder of the sheer amount of nuance (and possibility) that exists within a single class of technologies.  

The same can be said for polymers, of which there are a wide range of natural and synthetic polymers and an increasing number of hybrid formulations (e.g., polymer-polymer and polymer-lipid combinations, etc.). Given this diversity, I appreciated one speaker’s friendly reminder that it’s difficult to generalize the polymer field because manufacturing complexity, toxicity, biocompatibility, and efficacy all vary widely across each type.

As such, one of the fundamental challenges in navigating each new delivery technology will be seeing, differentiating, and acknowledging each “individual ‘tree’ from the [delivery technology] ‘forest’,” if you will, as well as (potentially) aligning around regulations and industrializing such a wide base of diverse technologies in the future.

BONUS Hot Take #4: To Unlock New mRNA Delivery Mechanisms, We Need More Negative Data

Secondly, the sheer amount of heterogeneity in each technology means there are still significant knowledge gaps that need to be filled via fundamental research — preferably outside of an academic environment for manufacturability/scalability, and compliance reasons. I know this is much easier said than done. We need money and time to invest in these forms of R&D, and investors’ willingness (or lack thereof) to support exploration of a less mature delivery technology will ultimately dictate each manufacturer’s investments. But, as one speaker surmised, a potential transition toward hybrid delivery technologies (e.g., liposomes with EVs or polymer-lipid combinations) in the future could necessitate more companies bringing multiple delivery technologies under their roofs earlier in development.

There’s the well-known saying in pharma: If you’re going to fail, fail early and fail fast. Of course, we’d all like to guarantee that our explorations into less mature delivery technologies would result in loads of positive data and a clear-cut path forward. But I appreciated one expert’s insistence that more early investments are essential because the production of negative data can be just as valuable for us forward. On the one hand, it can keep us grounded and cut through the noise of overly positive and/or less realistic generalities simplifying a delivery technology. But negative data will also be essential to help us as an industry discern which paths won’t be worth the time and investment risk in the space in the long run. And when it comes to nonviral delivery, the presentations during this BioPhorum event demonstrated there are still a lot of diverse paths down which we can venture.