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Next-generation programmable cell therapies for precision medicine

Nature Reviews Genetics (2026)Cite this article

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Abstract

Engineered cell therapies are transforming precision medicine by enabling real-time, context-responsive interventions that act upon disease-specific cues. Inspired by the success of CAR-T cells in oncology, next-generation platforms are being developed using diverse immune cells and stem cells to address a broader spectrum of diseases. These living therapeutics harness synthetic gene circuits to induce targeted cytotoxicity, to modulate the secretion of effector proteins or to coordinate both functions in response to endogenous signals or externally delivered molecular and physical triggers. Ex vivo engineering of autologous cells remains the norm, but challenges in scalability, cost and accessibility are fuelling efforts towards allogeneic products and in vivo reprogramming. Advances in targeted delivery — using viral vectors, mRNA-loaded nanoparticles and virus-like particles — are expanding the toolkit for direct programming of cells within the body. This Review discusses emerging strategies for engineering human cells with therapeutic functions, highlighting modular control systems, delivery innovations and the translational hurdles that lie ahead.

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Fig. 1: Engineering cells with therapeutic programs.
Fig. 2: Inducible control of target protein function at the DNA, RNA and protein levels.
Fig. 3: Enhancing cell therapies with synthetic biology.
Fig. 4: Autologous, ex vivo engineered cell therapies.
Fig. 5: Designing off-the-shelf allogeneic engineered cell therapies.
Fig. 6: In vivo programming of therapeutic cells.

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Acknowledgements

We thank A. Fussenegger-Aubel for advice on the figure design.

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Authors and Affiliations

  1. Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland

    Ana Palma Teixeira & Martin Fussenegger

  2. Département Génie Biologique, IUTA, Université Claude Bernard Lyon 1, Villeurbanne, France

    Dominique Aubel

  3. Faculty of Science, University of Basel, Basel, Switzerland

    Martin Fussenegger

Authors
  1. Ana Palma Teixeira
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  2. Dominique Aubel
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  3. Martin Fussenegger
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All authors contributed to all aspects of the manuscript.

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Correspondence to Martin Fussenegger.

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Nature Reviews Genetics thanks Melita Irving, Graham Lord, who co-reviewed with Isabella Barbutti, and Katayoun Rezvani, who co-reviewed with Rafet Basar, for their contribution to the peer review of this work.

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Glossary

Allogeneic cell therapies

Therapies using cells from a healthy donor and administered to a different recipient.

Autologous cell therapies

Therapies using the patient’s own cells, modified ex vivo and re-infused.

Encapsulation

The physical confinement of cells within semi-permeable materials that protect them from immune attack while allowing diffusion of nutrients, oxygen and therapeutic molecules.

Envelope protein

Viral surface protein embedded in the lipid envelope that mediates host-cell binding and membrane fusion, determining tropism and entry efficiency.

Immune reset

A transient therapeutic reprogramming of the immune system, with ablation of pathogenic cells, enabling immune reconstitution towards a healthier state.

Kill switches

Engineered safety mechanisms that trigger selective elimination of therapeutic cells to prevent adverse effects.

Logic gates

Engineered genetic circuits implementing Boolean rules (such as AND, OR, NOT, IF–THEN) so that effector functions occur only under specific combinations of molecular or environmental cues.

Priming

Transient ex vivo conditioning of cells to enhance therapeutic function without permanent genetic modifications.

Safe-harbour locus

Genomic site that supports stable transgene expression without disrupting endogenous gene function.

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Teixeira, A.P., Aubel, D. & Fussenegger, M. Next-generation programmable cell therapies for precision medicine. Nat Rev Genet (2026). https://doi.org/10.1038/s41576-026-00945-3

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