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  • Review Article
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Overcoming xenotransplantation barriers through gene editing and immunomodulation

Nature Reviews Bioengineering (2026)Cite this article

Subjects

Abstract

Xenotransplantation, the transplantation of organs, tissues or cells across species, offers a potential solution to the shortage of human organs for patients with organ failure. Porcine organs, which share key physiological, anatomical and immunological features with human organs, are currently the primary focus of preclinical and clinical xenotransplantation studies. In this Review, we examine major considerations and barriers in xenotransplantation, including species selection, hyperacute and acute rejection, and xenozoonosis, and discuss strategies to overcome these challenges through gene editing and immunomodulation. We emphasize the need to address antibody-mediated rejection, control complement activation, block co-stimulatory pathways, optimize graft preservation, develop high-fidelity endothelial models, identify additional porcine antigens, and promote immunohomeostasis and tissue repair. Furthermore, robust safety protocols, surveillance systems and mechanisms for ethical transparency are essential. The future success of xenotransplantation will depend on innovative technologies and refined models to resolve these complex challenges.

Key points

  • Solid organ xenotransplantation is being explored in clinical studies.

  • Antibody-mediated rejection, innate immune responses and complement activation remain key barriers in xenotransplantation.

  • Xenotransplantation can be improved by ensuring graft preservation, endothelial cell modelling, identification of pig antigens, establishment of immunohomeostasis and promotion of tissue repair.

  • Optimized lines of gene-edited pigs may be developed in tandem with recipient immunomodulatory strategies.

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Fig. 1: Generation of gene-edited pigs.
Fig. 2: Immunorejection of xenografts.
Fig. 3: The role of the endothelium and its glycocalyx in xenotransplantation.
Fig. 4: Immunobiology of cardiac xenotransplantation.
Fig. 5: Mechanism of co-stimulation interaction and its blockade.

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Acknowledgements

We would like to thank our laboratory and clinical team members, including T. Zhang, A. Hershfeld and B. Lewis, who contributed and supported the clinical transplantation of pig hearts to a baboon model and ultimately to the clinic. Funding is generously provided by public funding from NIH U19 AI090959 ‘Genetically-engineered Pig Organ Transplantation into Non-Human Primates’ and private funding by United Therapeutics. Additional funding was provided by public funding from NIH T32 5T32HL007698-26. The funders were not involved in the interpretation of data, the writing of this article or the decision to submit it for publication.

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  1. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    Andy Tully, Avneesh K. Singh, Javier Galindo, Bartley P. Griffith & Muhammad M. Mohiuddin

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  1. Andy Tully
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  2. Avneesh K. Singh
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  3. Javier Galindo
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  4. Bartley P. Griffith
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  5. Muhammad M. Mohiuddin
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All authors contributed equally to the preparation of this manuscript.

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Correspondence to Muhammad M. Mohiuddin.

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Competing interests

M.M.M. and B.P.G. received research funding from United Therapeutics, and M.M.M. also received funding from the National Institute of Allergy and Infectious Diseases, NIH (no. AI090959). Revivicor provided pigs in kind. Eledon and Kiniksa Pharmaceuticals provided anti-CD40L and anti-CD40 antibodies in kind for the transplantation. XVIVO provided cardiac preservation support. M.M.M. is also a consultant for Sanofi Pharmaceuticals.

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Nature Reviews Bioengineering thanks Paolo De Coppi, Kefeng Dou and Bruno Reichart for their contribution to the peer review of this work.

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Tully, A., Singh, A.K., Galindo, J. et al. Overcoming xenotransplantation barriers through gene editing and immunomodulation. Nat Rev Bioeng (2026). https://doi.org/10.1038/s44222-026-00412-y

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