Powering Cell Therapies With RNA: A New Code For Engineered Immunity

By Jyotsna Jajula, research assistant, Wayne State University

Cell therapies are transforming modern medicine, from CAR-T breakthroughs in oncology¹ to iPSC-based platforms for regenerative repair.³ Yet even with their therapeutic promise, many of these approaches still rely on viral vectors or permanent genome editing, methods that introduce complexity, cost, and regulatory friction. As the field matures, developers are looking for more flexible, transient, and scalable ways to engineer cellular function.

RNA is rapidly emerging as that programmable solution. Whether delivering synthetic mRNA for protein expression, modRNA for reprogramming, or guide RNAs for CRISPR editing, RNA enables precise but temporary control over gene function, without the risks of integration or viral packaging.^2,4

Beyond acting as a therapeutic payload, RNA is now being used as a core component of manufacturing and development pipelines in both immune and stem cell therapies.

RNA is also powering a new generation of engineered immunity. From streamlining iPSC reprogramming to tuning T cell function, RNA offers a write-run-delete model for cell therapy innovation that is faster, safer, and more programmable than ever before. As we enter 2026, the future of cell therapy may well be written in code: RNA code.

Why RNA Tools Are Redefining Cell Therapy Workflows

Cell therapies rely on precise manipulation of cellular function, whether that’s inserting a chimeric antigen receptor (CAR) into a T cell, reprogramming fibroblasts into induced pluripotent stem cells (iPSCs), or transiently activating immune pathways. Traditionally, such modifications have required integrating viral vectors (e.g., lentivirus, retrovirus) or genome-editing systems that pose both safety and regulatory challenges. These methods are often resource-intensive, slow to adapt, and difficult to scale cleanly for clinical-grade manufacturing.^5,6

RNA-based tools offer a radically different approach. Because RNA is inherently transient and non-integrative, it allows for time-limited expression of genetic payloads without permanent alteration to the genome. This makes RNA especially valuable in early-stage optimization and clinical workflows in which temporary signaling or short-term expression is sufficient, or even preferred. Synthetic mRNA, modRNA, self-amplifying RNA (saRNA), and guide RNAs (gRNAs) used in CRISPR/Cas9 systems all enable precise, controllable interventions across diverse cell types.^5,8

Beyond biological advantages, RNA supports a rapid design–test–iterate model. Developers can go from digital sequence to functional mRNA in days, without relying on packaging cell lines or viral production facilities. RNA’s cell-free synthesis and modularity align well with closed-system manufacturing and automation platforms^7,9 that are increasingly being adopted by CDMOs and internal CMC teams.

Ultimately, RNA’s flexibility makes it not just a therapeutic agent but a foundational tool in the evolving playbook of cell therapy engineering. By reducing timelines, simplifying quality control, and lowering biosafety barriers, RNA is redefining what’s possible, from discovery through GMP production.¹⁰

From Bench To Bioreactor, Manufacturing With RNA

The challenges of scaling cell therapies extend far beyond biology. As these therapies move from preclinical labs to GMP-compliant manufacturing suites, the complexity of viral vector production, stability testing, and quality control (QC) become a major bottleneck. Every step — vector generation, batch testing, and sterility assurance — adds time, cost, and regulatory scrutiny. The pressure to streamline these workflows has led developers to search for cleaner, faster alternatives.

RNA unlocks a fundamentally different manufacturing paradigm. Its production is enzyme-based, cell-free, and scalable using modular kits or automated synthesis systems. Unlike viral vectors, RNA does not require packaging cell lines, transfection reagents, or purification from infectious particles. This dramatically reduces biosafety hurdles and simplifies compliance with GMP and ISO standards.^9,10

Moreover, RNA integrates seamlessly with closed-system automation, an increasingly critical feature for reproducible and contamination-resistant manufacturing. In iPSC reprogramming, for instance, synthetic modified RNA can be delivered daily using electroporation or lipofection in feeder-free, xeno-free conditions.³ In CAR-T workflows, mRNA can encode receptors, safety switches, or costimulatory domains, enabling precision control without genome integration.⁵ Each of these RNA-based interventions can be standardized across batches, improving lot-to-lot consistency and easing tech transfer to CDMOs.⁷

By aligning with GMP expectations for modularity, traceability, and flexibility, RNA is not just solving biological problems; it’s solving operational ones. As more developers embrace platform-based thinking in cell therapy pipelines, RNA offers a plug-and-play modality that bridges scientific innovation with scalable execution.¹⁰

Use Case Spotlight: RNA-Driven Innovation Across Cell Therapy Types

The value of RNA tools becomes even clearer when viewed across different classes of cell therapies. While each platform (T cells, iPSCs, NK cells, γδ T cells) presents unique engineering challenges, RNA offers a modular toolkit that adapts to each case with precision and flexibility.

T Cells: Transient Engineering Without Genomic Integration

In autologous CAR-T workflows, mRNA electroporation is increasingly used to deliver chimeric receptors, cytokine payloads, or editing components without permanent genomic changes.⁵ This is especially useful during early-stage development, where rapid iteration and safety testing are paramount. Researchers can introduce synthetic mRNA encoding CAR constructs or CRISPR gRNAs, observe phenotypic outcomes, and optimize signaling domains without triggering regulatory red flags associated with viral integration.⁶

iPSCs: Non-Viral Reprogramming at Clinical Scale

Induced pluripotent stem cells (iPSCs) have traditionally relied on lentiviral or episomal vectors for reprogramming, but modRNA cocktails now offer a cleaner, xeno-free path to pluripotency.³ These synthetic RNAs encode reprogramming factors like OCT4, SOX2, KLF4, and c-MYC and can be delivered via daily transfection for just one to two weeks. This virus-free process is not only safer but also better suited for GMP workflows due to reduced QC burdens and batch variability.^7,10

NK & γδ T Cells: Functional Activation On-Demand

Beyond CAR-T, RNA is increasingly used to modulate innate-like immune cells such as natural killer (NK) cells and γδ T cells. These cell types often resist viral transduction, but can be transiently enhanced with mRNA-encoded stimulatory receptors, cytokines, or resistance genes.⁵ For example, mRNA delivery of IL-15 or NKG2D ligands can boost cytotoxicity without altering the long-term phenotype, preserving safety while increasing short-term efficacy.⁸

Across all these use cases, the common thread is control over timing, expression level, and reversibility. RNA doesn’t just enable engineering; it enables precision programming, tailored to the therapeutic goal and regulatory stage.

Barriers, Breakthroughs, And The Road Ahead

While RNA technologies offer a powerful toolkit for cell therapy engineering, they are not without challenges. Instability, immunogenicity, and delivery efficiency remain active areas of optimization, especially in primary immune cells and stem cells, where transfection efficiency and toxicity must be tightly balanced.^5,6 RNA’s transient nature, while advantageous for safety, can also limit long-term efficacy unless carefully timed or repeated.

To address these limitations, researchers are developing next-generation RNA formats and delivery platforms. Circular RNA (circRNA) is gaining traction for its enhanced stability and reduced innate immune activation, offering extended protein expression from a single dose.¹⁰ Virus-like particles (VLPs) and lipid nanoparticles (LNPs) are being adapted for ex vivo RNA delivery, providing gentler, more tunable alternatives to electroporation.^4,9 Other strategies include chemical modification (e.g., pseudouridine, 5mC) to reduce toll-like receptor activation² and lyophilization workflows to enhance shelf life and transportability.⁹

Looking ahead, RNA’s role in cell therapy is poised to expand far beyond transient payload delivery. We are likely to see the rise of RNA-enabled modular manufacturing systems, where programmable templates are synthesized on demand to suit evolving trial designs or patient needs.¹⁰ With the increasing push toward virus-free, rapid-turnaround platforms, RNA could become the “source code” for engineered immunity, standardized, secure, and infinitely reprogrammable.

Conclusion: RNA As Infrastructure For Engineered Immunity

As cell therapy continues to evolve, from autologous to allogeneic platforms, from oncology to regenerative indications, the need for flexible, programmable, and scalable engineering tools will only intensify. RNA is uniquely positioned to meet that demand. Once viewed solely as a therapeutic payload, RNA is now emerging as a core infrastructure layer: one that enables rapid design cycles, modular manufacturing, and tunable immune programming.¹⁰

By embracing RNA not just as a molecule but as a dynamic codebase, the field is moving toward a new generation of cell therapies that are safer, faster, and fundamentally more adaptable. Whether powering the next iPSC platform³ or transiently tuning cytotoxicity in T cells,⁵ RNA offers an elegant solution to the complexity of modern cell engineering.

In this new era, the most powerful tools in cell therapy won’t be permanent edits, they will be temporary instructions. And those instructions are increasingly being written in RNA.

References

1. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics, developing a new class of drugs. Nat Rev Drug Discov. 2014
2. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines, a new era in vaccinology. Nat Rev Drug Discov. 2018
3. Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010
4. Reichmuth AM, Oberli MA, Jeklenec A, Langer R, Blankschtein D. mRNA vaccine delivery using lipid nanoparticles. Ther Deliv. 2016
5. Kaczmarek JC, Patel AK, Kauffman KJ, et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to human T cells. Sci Adv. 2021
6. Wang HX, Song Z, Lao YH, et al. Nonviral gene editing via CRISPR/Cas9 delivery by membrane-disruptive and endosomolytic helical polypeptide. Proc Natl Acad Sci USA. 2018
7. Alapati D, et al. Non-viral delivery systems for CRISPR/Cas genome editing: recent advances and future perspectives. Expert Opin Drug Deliv. 2021
8. Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy. Science. 2018
9. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. The dawn of mRNA vaccines: The COVID-19 case. J Control Release. 2021;333:511–520.
10. Ramaswamy S, et al. Emerging RNA-based therapeutic platforms for cell and gene therapy. Mol Ther. 2021

About The Expert

Jyotsna Jajula holds a master’s degree in pharmaceutical sciences with a research focus on lipid nanoparticles, RNA stability, and targeted delivery systems. Her research focuses on optimizing biodistribution and immunocompatibility of RNA therapeutics across oncology, immunology, and gene therapy applications.