De-Risk Nucleic Acid Therapeutic Development With Strategic Outsourcing And Specialized Expertise

Although nucleic acid therapeutics (NATs) have been studied for decades, they are now experiencing momentum. Their ability to treat infectious diseases, cancer, and genetic disorders, combined with the clinical validation and regulatory success of COVID-19 mRNA vaccines has underscored the modalities’ potential. As confidence grows in the ability to design and manufacture NATs efficiently, developers are pursuing innovative treatment possibilities for patients.

However, bringing a NAT successfully to market requires specialized formulation and development knowledge. Due to the inherent instability of some of these molecules, NAT innovators need rigorous analytical approaches and formulation strategies to achieve adequate product stability and quality. As pharma companies prepare for development, they must account for the complexities of these modalities, avoid common pitfalls faced in the early stages, and identify strategies that improve stability, reduce risk, and accelerate progress on the path from IND to commercial success.

What Are NATs?

NATs encompass a broad class of therapeutics, ranging from small synthetic molecules such as small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) to larger nucleic acids like mRNA that require a lipid nanoparticle (LNP) or polymer-based delivery system to become a viable drug. NATs encompass multiple classes, each with their own distinct characteristics (Table 1).

Table 1. NAT categories and features.

Category	Typical Size	Examples	Key Features
Small NATs	< 30 nucleotides	ASOs, siRNA, miRNA, anti-microRNA oligonucleotides (anti-miRs), aptamers, single-stranded oligodeoxynucleotides (ssODNs)	Chemically synthesized, high purity, well-defined identity
Intermediate NATs	30 – 200 nucleotides	Guide RNAs (gRNAs), some aptamers, short regulatory RNAs	Often chemically synthesized, at upper size end enzymatic production possible
Larger NATs	> 200 nucleotides	mRNA, self-amplifying RNA (saRNA), circular RNA (circRNA), plasmid DNA	Enzymatically produced, often combined with a drug delivery system (e.g., LNP)

Developers must determine which approach best enables stabilization of these molecules and ability to reach their target tissue. This can include combinations of nucleic acids with, for example, LNPs, polymer-based delivery systems, or conjugation strategies such as N-Acetylgalactosamine (GalNAc) or antibody- or peptide-linked oligonucleotides.

Administration routes also vary by delivery system. For example, siRNA may use conjugates for subcutaneous delivery or LNPs for IV administration. Across the different categories of NATs, developers face manufacturing obstacles or may have questions with respect to regulatory requirements.

What Are The Common Development Pitfalls For NATs?

Consider some of the major development challenges that could hamper the success of early-phase NATs:

• Their instability can lead to chemical degradation, aggregation, and sensitivity to stress factors during processing. These qualities must be factored into the early stages of development via thorough characterization that aims to demonstrate product quality and prevention of chemical changes and unanticipated particle formation. However, these risks are often overlooked when companies lack sufficient analytical capabilities. 

• Development teams often lack a deep understanding of their delivery systems. For a NAT to be successful, pharma companies must have thorough knowledge of the organ or cells the delivery system is targeting and the mechanism of action. For LNPs, this requires identifying the appropriate lipid composition ratios and from there, effectively preparing the molecule for manufacturingand continued stability. Without robust delivery system experience, gathering this knowledge is difficult. 

• mRNA-based NATs in particular require cold-chain storage or lyophilized formulations to maintain stability. Many mRNA-based NATs are kept frozen, requiring expensive cold chain logistics across their life cycle. To improve accessibility, developers pivot to lyophilization, i.e., freeze-drying, which reduces the stringency for (ultra) cold-chain logistics but requires a complex formulation process and specialized expertise.  

• Manufacturing processes that are not scalable from small volume to commercial production. Though NAT development starts on small-scale, these manufacturing processes must eventually scale to accommodate stability studies, clinical studies, and commercial demand. Their complexity can make establishing large-scale manufacturing processes daunting.  

Strategic decisions around nucleic acid sequences and their modifications, delivery systems, formulations, and manufacturing processes early in development can prevent costly scale-up challenges downstream. With deep understanding and characterization of their products early on, teams will sidestep these obstacles, accelerate development, and secure a high-quality product and scalable production process.

What Advantages Does An Expert Partner Offer?

For most NAT developers, it would take years to establish the requisite expertise and infrastructure to develop their product in-house. Outsourcing product development, including formulation development, gives companies access to advanced analytic capabilities, delivery system expertise, and experienced scientific teams that can guide their development program toward commercial success, helping reduce timelines and mitigate risks.

At Coriolis Pharma, our scientists work across multiple modalities, including proteins, peptides, viral vectors, and NATs, and offer more than 12 years of dedicated experience in NAT development spanning mRNAs, ASOs, siRNAs, and nanoparticles like LNPs and polymer-based nanoparticles. We focus on collaborative partnerships that are built on clear communication and defined ownership, applying a problem-solving mentality that drives projects forward. These capabilities support analytical and drug product development from early research through commercialization. During early development, Coriolis assists pharma companies in understanding their molecule’s behavior and stability via advanced analytical and biophysical characterization, stress testing, and formulation development, which are critical for unstable and highly sensitive NATs like mRNA and oligonucleotide conjugates.

During preclinical and early clinical development, efforts focus on formulation development and optimization to transition toward more commercially viable products, including the potential shift from liquid to lyophilized formulations. Our team also evaluates primary packaging materials to determine how they interact with the product and to establish stability profiles.

Finally, in late-stage clinical development, formulations are refined to meet commercial requirements. At Coriolis we conduct GMP release testing of clinical and commercial batches, and maintain partnerships with high-quality, GMP-scale CDMOs that have the infrastructure for commercial scale-up. Our experts collaborate closely with these manufacturers to provide life cycle management and reformulation strategies as needed.

Coriolis’ adept staff is supported by a scientific advisory board that includes NATs experts, Dr. Gideon Kersten (Leiden University & Coriolis Pharma), as well as Ludwig Maximilian University of Munich professors, Prof. Dr. Olivia Merkel and Prof. Dr. Ernst Wagner. Coriolis’ longstanding experience with biologics development enables our team to continually prepare for the next cutting-edge modalities. Ongoing internal research initiatives support emerging technologies, along with contributions to the Cluster for Nucleic Acid Therapeutics Munich (CNATM), a consortium dedicated to translating NATs from academia into commercial applications.  

As new formulations emerge, Coriolis applies state-of-the-art analytical methods and development strategies to help advance novel modalities such as mRNA-LNPs and antibody-oligonucleotide-conjugates (AOCs). Each approach is tailored to the unique needs of a specific NAT program, rather than relying on a one-size-fits-all platform.

How Do Developers Ensure Speed And Precision From Early Phase To Commercialization?

NATs offer the potential to treat rare diseases and genetic disorders once considered intractable. Now, with the clinical and commercial pathways established, developers are setting their sights on manufacturing approaches that accelerate progress from IND to clinical milestones and commercialization. Achieving this requires early investment in stability, rigorous characterization, and scalable processes that support a successful path to market. At the same time, continuously refining the Quality Target Product Profile (QTPP) and applying key Quality-by-Design (QbD) principles helps ensure that critical quality attributes and process parameters are well understood early on to enable faster, more predictable development and scale-up.