The Future of mRNA Technology in Vaccine and Drug Development
Dr. Gilles Besin, Chief Scientific Officer at Orbital Therapeutics and early mRNA innovator
Dr. Kinkini Roy, Associate Director at Aviceda Therapeutics and expert in RNA drug delivery
Dr. Jieming Gao, Technical leader at CSL with deep expertise in the discovery, development, and manufacturing of mRNA-LNP drug products.
mRNA technology is transforming medicine, expanding beyond vaccines to target cancer, genetic disorders, and autoimmune diseases. This panel brings together three leading experts to explore the future of mRNA therapeutics, addressing advances in delivery, sequence design, regulation, and broader clinical applications.
Q1. How do you envision mRNA technology evolving over the next decade in terms of its therapeutic applications beyond infectious diseases?
Dr. Gilles Besin: mRNA technology is expanding into multiple therapeutic areas. Key applications include personalized cancer vaccines targeting tumor neoantigens, safer alternatives for rare genetic diseases, immune tolerance in autoimmune disorders, and enhanced regenerative medicine through cell reprogramming. Additionally, mRNA allows controlled production of therapeutic proteins, improving dosage management.
Q2. What are the current limitations in lipid nanoparticle (LNP) delivery systems for mRNA drugs, and how are researchers addressing them?
Dr. Kinkini Roy: The major limitation in LNP-based delivery is that LNPs primarily accumulate in the liver, limiting the ability to treat diseases in other organs. Other limitations are the immunogenicity, stability, and storage efficiency of LNPs.
For extra hepatic delivery, researchers are developing surface-functionalized LNPs for active targeting and using different ionizable lipids for passive targeting. LNP immunogenicity comes from PEG, so to decrease immunogenicity, researchers are developing PEG alternating polymers. To improve stability, researchers have already developed lyophilized LNP and other formulations with additives to improve room-temperature stability.
Q3. In your view, what are the critical factors that influence the success of mRNA-LNP formulations in terms of delivery efficiency and tissue specificity?
Dr. Jieming Gao: Success of mRNA-LNP delivery hinges on lipid composition (notably ionizable lipids), particle size (~60–100 nm), surface charge, and efficient endosomal escape. Modified mRNA enhances stability and minimizes immune activation. Tissue specificity is governed by lipid formulation, targeting ligands, RNA elements (e.g., miRNA-binding 3′-UTRs), and administration route (e.g., IV vs. IM). PEGylation modulates circulation time and immunogenicity. Formulation stability and manufacturing precision ensure consistency. While the liver is the default target, endogenous or active targeting enables delivery to other tissues.
Q4. With your experience in early RNA medicine development, how has the transition from DARPA-funded research to commercial mRNA vaccines transformed the innovation landscape?
Dr. Gilles Besin: The transition from DARPA-funded research to commercial mRNA vaccines, accelerated by the COVID-19 pandemic, has reshaped RNA medicine innovation. DARPA’s investments de-risked mRNA technology, validating its global effectiveness. Post-pandemic, modular vaccine platforms enable quick antigen swaps for diverse therapies. The pandemic also normalized public-private partnerships, fostering long-term innovation. Emergency use authorizations expedited regulatory processes, enhancing collaboration between regulators and RNA firms. The success of mRNA has attracted talent and spurred the emergence of new startups, while mRNA is now recognized as a strategic asset for national health, leading to investments in domestic production capabilities. In summary, DARPA's early support has evolved into a mature, platform-driven biotech frontier, integral to global research and health security.
Q5. How can mRNA sequences be engineered to improve translation efficiency and control unwanted immune responses in non-vaccine therapeutics?
Dr. Kinkini Roy: Engineering mRNA sequences for non-vaccine therapeutics involves a careful balance between maximizing translation efficiency and minimizing immune activation. The key strategies for these are Codon Optimization, Untranslated Region (UTR) Engineering, Nucleotide Modifications, 5’Cap and 3’ polyA Tail Optimization, secondary structure control by avoiding stable hairpins or structures near the 5′ end that hinder ribosome scanning along with removing immunostimulatory motifs.
Q6. Given your expertise in clinical-scale nanoparticle manufacturing, what are the key challenges in scaling mRNA therapies under cGMP conditions?
Dr. Jieming Gao: Scaling mRNA therapies under cGMP conditions poses key challenges, including the absence of standardized production guidelines, high costs of cGMP-grade reagents for IVT, and the need for robust yet flexible scale-up and scale-down capabilities. Additional issues include supply chain limitations and evolving regulatory frameworks. Overcoming these challenges requires strong collaboration among industry, regulators, and academia, advances in enzyme engineering, and implementation of rigorous quality control to ensure consistent, scalable, and compliant production of clinical-grade mRNA therapeutics.
Q7. How do you compare the immune durability of mRNA-based vaccines versus traditional platforms in long-term pathogen protection?
Dr. Gilles Besin: mRNA vaccines induce strong initial antibody levels, but these decline within 4–6 months, requiring boosters. Traditional vaccines, especially live-attenuated ones, can offer lifelong immunity. mRNA vaccines generate robust T-cell responses with a focus on a single antigen, while traditional vaccines provide broader epitope exposure. They are effective for boosting and promote durable memory B cells.
Q8. What role do targeted drug delivery systems play in expanding the scope of mRNA-based therapies, particularly for chronic diseases?
Dr. Kinkini Roy: Targeted drug delivery systems are essential in expanding the therapeutic potential of mRNA-based therapies for chronic diseases, where safe, repeated, and tissue-specific delivery is crucial. Tissue-Specific Targeting: Chronic diseases often affect specific tissues. These could be targeted by particular surface ligand-decorated LNPs. These ligands could be antibodies or peptides for specific tissue targeting. Early mRNA therapies were largely liver-targeted. Targeted delivery systems allow expansion to CNS (e.g., for Parkinson’s, ALS), Heart and skeletal muscle (e.g., for cardiomyopathies, muscular dystrophies), Lung (e.g., for cystic fibrosis)
Q9. How do you foresee the use of mRNA-LNP systems in gene editing applications like CRISPR evolving in the next five years?
Dr. Jieming Gao: Over the next five years, mRNA-LNP systems will drive progress in CRISPR-based gene editing, particularly for rare genetic disorders and persistent infectious diseases. Advancements will include improved precision, reduced off-target effects, acceptable toxicity and immunogenicity at therapeutic doses, and enhanced safety with next-gen CRISPR tools. AI-driven optimization will further refine safety and efficacy. As regulatory pathways mature, these innovations will greatly boost the clinical applicability, safety, and therapeutic potential of gene editing therapies.
Q10. What are the major scientific barriers to developing self-amplifying mRNA (saRNA) therapeutics for broader use cases?
Dr. Gilles Besin: Self-amplifying mRNA (saRNA) represents a significant evolution in mRNA technology, promising reduced dosage requirements and enhanced immune responses. However, several challenges hinder its broader therapeutic application beyond vaccines: Delivery complexity and payload size, innate immune activation and reactogenicity, manufacturing and scalability, lack of regulated expression control, host and cell-type specificity, and regulatory and safety challenges.
Q11. How are regulatory agencies responding to the complexities of novel mRNA formulations in non-vaccine drug development?
Dr. Kinkini Roy: Regulatory agencies are continuously evolving—they're building flexible, science-driven pathways to assess novel mRNA formulations, especially as the field moves beyond vaccines into chronic disease treatments, oncology, and rare disorders. However, they also demand rigorous characterization and robust safety data, particularly due to the novelty of repeat dosing, delivery systems, and immunogenicity concerns
Q12: How important is mRNA sequence optimization in reducing dose frequency and improving therapeutic window?
Dr. Jieming Gao: mRNA sequence optimization is crucial for reducing dose frequency and enhancing the therapeutic window. It boosts protein expression and stability through codon and UTR optimization, while modified nucleosides and uridine depletion lower immunogenicity. These improvements enable effective outcomes at lower doses, reducing side effects and prolonging therapeutic effects. Additionally, optimized sequences enhance compatibility with delivery systems, supporting targeted delivery. Overall, sequence optimization is essential for improving efficacy, safety, and dosing efficiency in mRNA therapies.
Q13. In terms of mRNA therapeutics, how crucial is early immunological profiling in predicting treatment efficacy?
Dr. Gilles Besin: Ans: Early immunological profiling is absolutely critical in mRNA therapeutics—not just for predicting treatment efficacy, but for guiding design, dosing, safety, and long-term success. This importance stems from mRNA’s dual role: it is both a delivery vehicle for protein expression and a potent immunological signal, especially through innate immune sensors.
Q14. What role can computational tools and AI play in accelerating formulation development and predicting delivery outcomes for mRNA drugs?
Dr. Kinkini Roy: Computational tools and AI are accelerating every stage of mRNA therapeutic development. During rational design, AI models can help design mRNA sequences with optimal codon usage for high translation efficiency and RNA folding algorithms of secondary structures that affect translation. Machine learning (ML) is used to optimize lipid compositions for LNPs to improve cell targeting, endosomal escape, and safety and to predict structure-activity relationships (SAR) between lipid chemistry and delivery efficiency.
Author Bio
Dr. Gilles Besin is the Chief Scientific Officer at Orbital Therapeutics, leading the development of next-generation RNA medicines. With over 15 years in immunology and vaccine development, he previously served as Head of Discovery at Affinivax, advancing vaccines for pathogens like Staphylococcus aureus and SARS-CoV-2. Earlier, at Moderna, he led immunology efforts focusing on mRNA delivery systems and T cell modulation. Dr. Besin also contributed to early mRNA vaccine research under DARPA, collaborating with Sanofi Pasteur and CureVac.
Dr. Kinkini Roy is the Associate Director of Formulation Development at Aviceda Therapeutics, a clinical-stage biotech company in Cambridge, Massachusetts. With over 17 years of experience, she has contributed to multiple industries through her leadership and innovation. Her expertise includes therapeutics, targeted drug delivery, controlled release, and RNA delivery. She holds an MS in Biotechnology, a PhD in Chemistry from University of South Carolina, Columbia, USA and completed her postdoctoral training at University of Massachusetts, Amherst, Polymer Science and Engineering.
Dr. Jieming Gao is a nanoparticle formulation expert with over 20 years of experience. He specializes in LNP drug development for mRNA vaccines, CRISPR, and oligonucleotide therapeutics. His expertise spans from early discovery to GLP/cGMP manufacturing, with a strong track record of successful IND filings and clinical trials.
