The Rise of RNA Platforms in Biologics and Immuno-Oncology: A New Era in Therapeutics

Over the past decade, RNA-based technologies have transitioned from the fringes of biotech to center stage, catalyzed by the success of mRNA vaccines during the COVID-19 pandemic. But this surge is just the beginning. Today, RNA platforms are rapidly evolving to support a new wave of innovation in biologics and immuno-oncology (IO), unlocking applications that were previously difficult to achieve with conventional biologics or small molecules.

One of the most notable shifts in the RNA space is the expansion beyond messenger RNA (mRNA) into a broader spectrum of RNA modalities. While mRNA remains a powerhouse for expressing therapeutic proteins and tumor antigens, especially in vaccine formats, researchers are now leveraging other types of RNA such as small interfering RNA (siRNA), short hairpin RNA (shRNA), self-amplifying RNA (saRNA), microRNA (miRNA) mimics and inhibitors, and more recently, circular RNA (circRNA). Each of these serves a different function. For instance, siRNA and shRNA are being harnessed to silence genes that contribute to immune suppression in the tumor microenvironment, such as those encoding PD-L1 or VEGF. On the other hand, miRNA modulators can fine-tune immune cell differentiation and inflammatory signaling pathways. The emergence of saRNA, which includes replicase elements that allow it to amplify itself within the cell, offers the promise of achieving longer-lasting protein expression with significantly lower doses—a crucial advantage for chronic diseases or large-scale vaccination efforts. Circular RNA, with its covalently closed loop structure, is gaining traction for its enhanced stability and resistance to exonuclease degradation, making it a promising next-generation platform for sustained therapeutic expression.

However, regardless of the RNA type, delivery remains a central challenge and an area of intense innovation. Traditional delivery approaches have been vastly improved by the widespread adoption of lipid nanoparticles (LNPs), which encapsulate RNA molecules and facilitate their uptake into cells. The composition of LNPs is now being optimized with newer generations of ionizable lipids that improve biocompatibility, transfection efficiency, and reduce off-target toxicity. Moreover, scientists are exploring the addition of targeting ligands on the surface of LNPs to guide them to specific immune cells like dendritic cells or T cells. Beyond LNPs, natural carriers such as exosomes—tiny vesicles released by cells—are gaining attention for RNA delivery due to their low immunogenicity and inherent targeting properties. Other platforms, including polymeric nanoparticles and injectable hydrogels, are being studied for their potential to offer controlled, sustained release of RNA therapeutics. In parallel, tumor-penetrating peptides are being conjugated to RNA carriers to enhance tissue penetration and facilitate delivery directly into the tumor bed—an approach that could revolutionize local immunotherapy and reduce systemic side effects.

These delivery advances are crucial because RNA platforms are now being actively developed for an array of immuno-oncology applications. One of the most promising avenues is the use of mRNA to develop cancer vaccines. These vaccines can be designed to encode neoantigens—unique antigens arising from tumor-specific mutations—or shared tumor-associated antigens. By delivering these sequences to antigen-presenting cells, mRNA vaccines can stimulate both CD8+ cytotoxic and CD4+ helper T cell responses against tumors. Companies like BioNTech and Moderna are already in late-stage clinical trials evaluating personalized mRNA cancer vaccines in combination with immune checkpoint inhibitors. Notably, the Moderna–Merck collaboration reported positive results in a Phase 2b study showing that their mRNA vaccine candidate, mRNA-4157/V940, in combination with pembrolizumab significantly reduced the risk of recurrence or death in melanoma patients compared to pembrolizumab alone (Moderna, 2023). This underscores how RNA can synergize with existing immunotherapies to enhance antitumor immunity.

Another powerful use of RNA in IO involves the local expression of immune-stimulating cytokines such as IL-12, IL-15, and IFN-α directly in the tumor microenvironment. Systemic administration of these cytokines often results in unacceptable toxicity; however, RNA platforms allow for localized, transient production of cytokines at the tumor site, minimizing systemic exposure and adverse effects. Clinical trials are underway exploring this concept, with early-stage studies showing enhanced tumor infiltration by T cells and natural killer (NK) cells, and improved tumor control.

RNA is also enabling new strategies for engineering immune cells in vivo. Traditional chimeric antigen receptor (CAR) T cell therapies require complex ex vivo manipulation, including isolation, genetic modification, expansion, and reinfusion of T cells—a time-consuming and expensive process. Researchers are now exploring the use of mRNA to directly deliver CAR constructs into T cells in vivo. This approach has the potential to simplify manufacturing, reduce costs, and increase accessibility. Companies like Cartesian Therapeutics and Umoja Biopharma are actively developing such in vivo cell reprogramming strategies using RNA.

Additionally, gene silencing approaches using siRNA and antisense oligonucleotides (ASOs) are being leveraged to modulate immune checkpoints and other immunosuppressive mechanisms. For instance, targeting PD-L1 expression in tumor cells using siRNA can sensitize tumors to immune checkpoint blockade. This is especially valuable in “cold” tumors that are non-inflamed and typically resistant to immunotherapy. In parallel, efforts are underway to silence genes in regulatory T cells or myeloid-derived suppressor cells to dismantle the immunosuppressive tumor milieu.

To support these varied applications, the RNA manufacturing ecosystem is also evolving. Unlike protein biologics, RNA production is cell-free and scalable. In vitro transcription (IVT) systems enable rapid and GMP-compliant production of RNA payloads, with the potential for customization and personalization at unprecedented speeds. Advances in automation, digital design, and synthetic biology are accelerating this transformation. Artificial intelligence (AI) and machine learning (ML) tools are being used to optimize codon usage, secondary structure, and untranslated regions (UTRs) in RNA sequences to enhance translation efficiency, reduce immunogenicity, and increase stability. In addition, thermostable RNA formulations are under development to alleviate cold-chain storage requirements, which could broaden global access to RNA-based therapies, particularly in low-resource settings.

Looking forward, the future of RNA platforms in biologics and immuno-oncology is remarkably bright. One major area of development is the design of multi-antigen RNA vaccines to prevent tumor escape via antigen loss. Combinatorial approaches that integrate RNA therapeutics with monoclonal antibodies, antibody–drug conjugates (ADCs), or small molecule inhibitors are being pursued to amplify the immune response and overcome resistance mechanisms. Moreover, synthetic biology is enabling the creation of “smart” RNA circuits—programmed logic gates encoded into the RNA payload—that can activate therapeutic gene expression only in the presence of specific tumor-associated signals, thus improving safety and specificity. Such intelligent RNA payloads could differentiate tumor from normal tissue more effectively than traditional vectors.

In conclusion, RNA technologies are reshaping the landscape of biologics and immuno-oncology by providing versatile, programmable, and scalable solutions to some of the field’s most persistent challenges. As delivery systems improve and the biology of the tumor microenvironment becomes clearer, RNA-based platforms are poised to not only complement but also transform the standard of care in cancer therapy. Whether it’s through personalized vaccines, localized cytokine expression, or in vivo immune cell programming, RNA therapeutics are at the frontier of a more adaptive, precise, and effective approach to fighting cancer.

References:

1. Moderna Press Release: Moderna and Merck Announce Positive Results for mRNA-4157/V940 and Keytruda in Melanoma

2. Nature Reviews Drug Discovery, 2022 – "The mRNA Vaccine Revolution: From COVID-19 to Cancer"

3. Nature Cancer, 2023 – "mRNA-based Cancer Immunotherapies: Challenges and Prospects"

4. BioNTech Investor Reports – https://investors.biontech.de/

5. Frontiers in Immunology, 2021 – "Delivery Systems for mRNA-Based Vaccines and Therapeutics"