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Xenotransplantation, the use of genetically modified pigs as organ donors, is entering clinical trials in kidney transplantation. Although the medical community has long considered xenotransplant a potential solution to the organ shortage, the perspective of potential recipient's is not well described. We distributed a survey to patients > 18 years of age on our kidney transplant waitlist assessing the following: demographics, insurance status, current waitlist status, transplant history, knowledge of xenotransplantation and recent xenotransplant news, willingness to accept a xenokidney, and reservations regarding xenotransplantation. Surveys were administered through three different modalities: email, electronic medical record patient portal, and physical mailings. A total of 717 patients were surveyed between April and June 2024. Quantitative statistical analysis was performed as well as sentiment and thematic analysis of free-text responses. Of 717 eligible individuals, 79 responses were received (response rate 11%), 59% were electronic and 41% were sent through physical mail. Respondents were 42% female, 25% African American, 85% with at least some college education, 46% with public insurance, and 58% reported religion as very important. Most respondents noted some awareness of xenotransplantation (77%) and many expressed a favorable impression (62%). Survey modality demonstrated a racial difference in response, with African American patients more likely to respond via physical mail (p = 0.014). Overall, the majority of respondents expressed a willingness to accept a xenokidney if outcomes were comparable to allografts (81%) or as a bridge to allotransplantation (65%), with similar findings on the sentiment and thematic analysis. The most common concerns expressed included organ rejection and incompatibility (30%), anxiety over the lack of long-term outcome data (25%) and organ durability (20%). Most patients on our kidney transplant wait list reported positive attitudes toward xenotransplantation and were willing to consider it under various circumstances, independent of anticipated time to transplant or reported time on the wait list. Knowledge of recent transplant events appeared to influence patient perceptions of xenotransplant. Using multiple survey methods was important to capture a sample more representative of our waitlist.

Combined renal and islet xenotransplantation could provide a durable treatment for end-stage diabetic nephropathy. In this feasibility-focused study, we evaluated two complementary approaches for clinical translation: (1) pre-vascularized composite islet-kidney (I-K) grafts and (2) sequential islet-after-kidney xenotransplantation with vascularized thymic lobe (VTL) co-transplantation as an adjunct immune tolerance strategy. Composite I-K grafts were generated in nine MHC-matched, minor-antigen-mismatched miniature swine pairs by implanting adult porcine islets beneath the renal capsule of juvenile kidney donors followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and VTL xenotransplantation, followed by streptozocin-induced diabetes and intraportal adult porcine islet infusion from a separate donor. Renal/metabolic function, porcine C-peptide, histology, and immune profiling were assessed. Composite I-K grafts demonstrated limited islet survival with peri-islet inflammation on histology at the graft preparation stage and were not advanced to pig-to-NHP xenotransplantation in this study. Sequential islet-after-kidney transplantation restored insulin-independent euglycemia in all recipients. Porcine C-peptide was detectable in the long-term survivor with intrahepatic insulin-positive islets at necropsy. Infection-associated thrombotic microangiopathy limited survival in two animals; in the 180-day survivor, anti-porcine hypo-responsiveness and evidence of thymopoiesis within the VTL graft were observed. In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.

Xenotransplantation of porcine cells, tissues or organs offers a promising strategy to address the critical shortage of human donor organs. However, cross-species pathogen transmission, instant blood-mediated inflammatory reaction (IBMIR)-related liver injury, chronic over-immunosuppression, and long-term safety remain major challenges in porcine islet xenotransplantation. In this study, we performed a clinical trial aimed to evaluate the biosafety of neonatal porcine islet xenotransplantation in patients with type 1 diabetes. Ten recipients were assigned to two groups receiving non-encapsulated neonatal islet cell clusters via the jugular-hepatic-portal vein at mean doses of 6354 ± 835 IEQ/kg and 11 600 ± 1100 IEQ/kg, respectively. Donor pigs originated from a highly inbred, PERV-C-negative colony reared in designated pathogen-free (DPF) conditions, with rigorous pathogen and PERV screening. Immunosuppression included mycophenolate mofetil, tacrolimus, belatacept, and autologous regulatory T-cell therapy, combined with tocilizumab. Continuous low-dose heparin was infused via a portal vein catheter was used for 7 days as anticoagulation therapy. Recipients and spouses were monitored for over 5 years, with 7 followed for more than 10 years. No PERV transmission or transplant-related infections were detected in any recipient or contact during long-term follow-up. The procedure was safe and well-tolerated, with only transient liver function and coagulation changes and mild adverse events. Both groups showed reduced exogenous insulin requirements and markedly lower hypoglycemia incidence, with better glucose control in the higher-dose group. This study demonstrates that DPF PERV-C-free neonatal porcine islet xenotransplantation is biologically safe and partially effective, supporting its value as a reliable donor source and foundational platform for advancing clinical islet xenotransplantation. ClinicalTrials.gov identifier: NCT03162237.

Xenotransplantation has entered a phase of accelerated clinical translation, necessitating renewed international consensus on governance, ethics, safety, and regulatory oversight. In September 2025, the International Xenotransplantation Association (IXA), in partnership with The Transplantation Society (TTS) and with engagement from the World Health Organization (WHO), convened a Global Consultation in Geneva to review, update, and harmonise international guidance for clinical xenotransplantation. This IXA consultation marked the twentieth anniversary of the first WHO Xenotransplantation Advisory Consultation in 2005 and built upon the foundational principles established through the Changsha Communiqué (2008, 2011 and 2018) and subsequent IXA and WHO-led initiatives. Responding to rapid scientific advances, including some defined donor genetic standards, improved immunosuppression, enhanced biosecurity, and strengthened infectious disease surveillance, the IXA undertook an 18‑month, structured, evidence‑based revision process. Seven expert working groups, comprising approximately forty internationally recognised specialists from fourteen countries, reviewed developments across source animal standards and biosecurity, clinical trial design and oversight, immunosuppression and patient management, infectious disease risk and surveillance, ethical and legal frameworks, international governance, and emerging technologies. Draft recommendations were further refined through iterative consultation and plenary deliberation at the in‑person meeting held in Geneva, September 2025. The consultation proposed updated Principles and Recommendations directed to WHO, national regulators, investigators and sponsors, and the IXA/TTS communities. Key elements include proportionate risk benefit assessments, robust donor and recipient surveillance, long‑term biobanking and monitoring, transparency and public engagement, harmonised regulatory oversight consistent with existing allotransplantation frameworks, and equitable access to future clinical applications. The revised guidance aligns with contemporary regulatory expectations of major international jurisdictions regulatory authorities including (AEMPS, ANMAT, CONABIA, CONFEPRIS, EMA, FDA, GTAC, HC, IEC, INCUCAI, Medsafe, MFDS, MHRA, MHLW, NMPA, NZGTAC, MFDS, MHRA, TGA); and consolidates international consensus at a critical juncture for the field. This IXA Global Consultation provides an authoritative, forward‑looking framework to support safe, ethical, and globally coordinated clinical xenotransplantation as it transitions from experimental innovation to regulated clinical practice.

The objective of this review is to map and synthesize the existing literature regarding informed consent for porcine islet xenotransplantation for the treatment of Type 1 Diabetes. The search was conducted in May 2025 through the following databases: PubMed, SCOPUS, EMBASE, and CINAHL. Broad search strings were used to combine the text words "islet" AND "xenotransplantation" AND "consent" or similar permutations and combinations. Peer-reviewed articles were included if they were published between January 1990 and May 2025 and written in English. The final search results were manually exported to a reference manager system (Zotero), and the PRISMA-ScR flow diagram was created to depict the data extraction process. From 134 sources, 7 articles met eligibility for this scoping review. Although clinical studies have been sporadically conducted, there is a lack of literature describing informed consent for islet xenotransplantation. This review highlighted a scarcity of scholarly discourse and published guidance on informed consent specifically in the context of islet xenotransplantation.

As the chronic shortage of human donor organs becomes an undeniable clinical reality, xenotransplantation has transitioned from a theoretical concept to the threshold of clinical integration. Recent successful pig-to-human kidney trials signify a pivotal milestone, shifting the scientific focus from feasibility to long-term sustainability and systemic implementation. This review critically evaluates the current status and future trajectory of xenotransplantation, challenging the "more is better" paradox of genetic engineering. It emphasizes the minimum viable edit set and the physiological superiority of miniature pigs overgrowth hormone receptor knockout models. Furthermore, the paper outlines a Korean-style governance model, integrating advanced digital transformation and specialized infrastructure. Key proposed strategies include (1) digital monitoring: implementing a noninvasive surveillance system utilizing donor-derived cell-free DNA, digital twins, and AI-driven early warning systems; (2) blockchain integration: establishing data integrity and tokenomics-based patient compliance through a sovereign medical coin system to incentivize lifelong surveillance; (3) infrastructure innovation: introducing the Hybrid Hospital Model, featuring a sterile barrier window between porcine and human surgical suites to achieve a zero-ischemia workflow. Finally, the study stresses the necessity of a Xenotransplantation Special Act and the collaboration between public organ procurement organizations and specialized private contract research organizations. By combining genetic minimalism and a robust legal framework, South Korea can establish itself as a global standard setter, transforming xenotransplantation into a standardized, manageable precision medical service.

Recent progress has been made toward introducing gene-edited (GE) pig heart and kidney xenotransplantation into clinical practice. In particular, the outcomes of GE pig kidney transplantation have been promising, with three recipients currently surviving between 3 and 9 months after transplantation. These encouraging results highlight the growing feasibility of xenotransplantation as a solution to the shortage of human donor organs. In the United States and many other countries, nearly half of all patients on kidney transplant waiting lists are diabetic. Individuals with diabetic nephropathy often achieve better outcomes when they receive both kidney and islet allotransplants, as this combination restores renal function and improves glucose control. Therefore, such patients would be ideal candidates for combined GE pig kidney and islet xenotransplantation. Because immunosuppressive therapy is essential to maintain a kidney graft, performing a simultaneous islet transplant is clinically justifiable. Studies in nonhuman primates have demonstrated that porcine islet transplantation can achieve long-term glucose regulation, supporting its translational potential. For the foreseeable future, until complications such as post-transplant proteinuria are fully resolved, we propose that patients with diabetic nephropathy receive a human kidney allotransplant in combination with a GE pig islet xenotransplant to optimize outcomes and improve long-term metabolic stability.

Swine leukocyte antigens (SLA) may be a new type of xenoantigen. Previous studies on SLA have primarily focused on their cross-reactivity with HLA. However, the role of SLA in stimulating xenogeneic immune responses after xenotransplantation remains unclear. In our recent kidney xenotransplantation study in rhesus monkeys using GTKO/hCD55 or GTKO/β4GalNT2KO/hCD55/hTBM pigs as donors, 5 of 13 recipients experienced early AMR accompanied by a marked increase in anti-donor pig antibodies. Flow cytometry analysis showed that the terminal sera of these recipients contained significant de novo anti-SLA antibodies, as evidenced by reduced antibody binding to GTKO/SLA-I/II KO pig PBMCs. Using GTKO/β4GalNT2KO pAECs with or without pIFN-γ stimulation as target cells, we found that the binding levels of the terminal sera to pAECs were positively correlated with SLA expression. IP-MS analysis identified multiple SLA class I and class II epitopes targeted by recipient IgG antibodies, with SLA-2 emerging as a dominant immunogenic antigen. In addition, xenogeneic MLR assays revealed that deletion of SLA, particularly SLA class II, markedly attenuated human anti-pig T-cell proliferation. These results demonstrate that induced anti-SLA antibodies can be generated in the early period after pig-to-monkey kidney xenotransplantation and may play a significant role in the development of AMR.

For the management of type 1 diabetes, islet xenotransplantation has emerged as a potential alternative to lifelong insulin therapy or islet allotransplantation. However, this progress raises significant ethical questions that warrant further exploration. This article will examine the ethical landscape of islet xenotransplantation, highlighting points of convergence and distinction with solid organ xenotransplantation. We focus on four key areas: (i) animal welfare, including the ethical implications of sourcing large numbers of pigs per recipient; (ii) pediatric considerations, given the lifelong impact of early interventions, and the increasing prevalence and burden of pediatric diabetes; (iii) informed consent and obligations for long-term monitoring including sample retention; and (iv) strategies for inclusive public and patient engagement to build trust and transparency.

Xenotransplantation offers a promising solution to the shortage of human organs for transplantation but requires overcoming numerous immune responses-particularly those mediated by the innate immune system through natural killer (NK) cells and macrophages. This review examines advances demonstrating that the expression of human leukocyte antigen E (HLA-E) on porcine cells contributes to reduce cellular xenograft rejection. HLA-E expression partially inhibits both direct NK cell cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), while also attenuating macrophage-mediated lysis. Furthermore, perfusion of transgenic porcine organs expressing HLA-E with human blood resulted in significantly less tissue damage compared to wild-type counterparts, thereby confirming the protective effect of HLA-E against innate immunity. Inhibition of NK cell activation can be further enhanced by co-expression of HLA-G and HLA-E. These findings confirm the potential of HLA-E and HLA-G expression as a complementary strategy in the design of immune-compatible porcine organs for clinical xenotransplantation.

The persistent shortage of donor organs has renewed interest in porcine xenotransplantation as a scalable alternative to human allotransplantation. Advances in genome engineering and immunomodulation have accelerated the field from experimental proof-of-concept toward early clinical translation. This review summarizes recent progress in donor pig genetic modification, targeted immunosuppressive strategies, surgical implementation, and rejection surveillance. Multigene-edited pigs lacking major carbohydrate xenoantigens and expressing human complement, coagulation, and cytoprotective regulators have substantially reduced hyperacute and acute vascular rejection. In parallel, costimulation blockade targeting the CD40/CD154 pathway has enabled prolonged graft survival in non-human primates and supported the first pig-to-human heart and kidney transplants. Improvements in organ preservation, recipient selection, and molecular monitoring, including circulating graft-derived DNA and multi-omic profiling, have further strengthened translational readiness. Complementary porcine models, including pig-to-pig transplantation and vascularized composite tissue transplantation, provide valuable platforms for studying tolerance induction, surgical refinement, and long-term graft biology. Human-to-pig chimerism has also been explored as a potential strategy to promote immune tolerance and improve graft compatibility. Despite these advances, major barriers remain, including delayed antibody-mediated rejection, coagulation dysregulation, innate immune activation, infectious safety, and regulatory challenges. Porcine xenotransplantation has now entered an early clinical era, with durable immune control and long-term safety representing the next decisive milestones.

The purpose of this review is to summarize the most influential and conceptually significant publications from the past 2 years, including substantial 2026 publications, and to identify emerging directions likely to shape xenotransplantation and regenerative medicine in the near future. Advances in artificial intelligence (AI) now support more structured anticipation of future developments by integrating patterns across experimental, computational, and translational research. The field is approaching a potential inflection point in which increasingly capable AI systems, potentially approaching artificial general intelligence, may accelerate the design of stem-cell-derived tissues and progressively more complex organ constructs. In addition, scientific communication is evolving toward formats that support machine-assisted analysis and AI-driven knowledge synthesis. Multiple developments signal significant expansion across xenotransplantation and regenerative medicine, driven by innovations in gene editing, multimodal data integration, and AI-enabled prediction and decision-support systems. These advances will help to broaden access to transplantable organs and increase the scale and impact of the field across clinical practice, research, and workforce domains. Together, these trends suggest that AI-enabled regenerative and xenogeneic strategies may meaningfully reduce the organ shortage and support future progress toward precision-engineered organ replacement.

Inflammatory responses have been shown to contribute significantly to the rejection of grafts in both allo- and xenotransplantation. In particular, they play a pivotal role in promoting endothelial activation, complement deposition, and thrombosis, thereby compromising the graft function. In this study, we investigated the molecular and functional properties of genetically modified porcine aortic endothelial cells (PAECs) that carry a knockout of α1,3-galactosyltransferase and express human CD46 and thrombomodulin (3GM) in xenogeneic and inflammatory environments. Transcriptomic profiling revealed that these genetic modifications effectively reduced the intrinsic inflammatory and procoagulant phenotype of 3GM PAECs. Under xenogeneic activation, 3GM PAECs also exhibited minimal cellular responses distinct from those of wild-type (WT) PAECs, along with robust protection from the activation of the complement and coagulation systems. However, under inflammatory conditions, 3GM and WT PAECs showed more aligned transcriptional and functional profiles characterized by pronounced upregulation of proinflammatory and prothrombotic pathways, increased complement deposition, and a shift toward a more procoagulant state. This loss of protection during inflammatory conditions was associated with the induction of inflammatory and procoagulant mediators, including PAI-1 and uPAR, despite stable transgene expression. Collectively, these insights enhance our understanding of the complex interplay between inflammation, complement, coagulation, and immune regulation in xenotransplantation. Our findings further emphasize the importance of incorporating both genetic and pharmacologic strategies targeting inflammatory pathways to enhance graft compatibility.

Xenotransplantation holds promise for addressing the organ shortage crisis. Multi-genetic modification of pigs, such as knockout of three carbohydrate antigen-related genes and expression of immunoprotective proteins, can significantly improve xenograft survival. However, existing multi-gene modification strategies face challenges: transposon-based transgenic technology may lead to unstable expression, while exogenous promoters used in site-specific integration strategies are susceptible to epigenetic silencing, making it difficult to maintain long-term, stable expression levels. Therefore, developing a donor pig model capable of achieving stable and long-lasting multi-gene expression is a critical need in the field. CRISPR-Cas9 technology was used to knockout three major glycan antigen genes (GGTA1, CMAH, β4GalNT2) to eliminate hyperacute rejection. Subsequently, four human protective genes (hCD55, hCD46, hTHBD, hEPCR) were site-specifically integrated into the porcine Rosa26 safe-harbor locus. Their expression was driven by the porcine endogenous Rosa26 promoter and the THBD core promoter, respectively, to ensure long-term stable and tissue-specific expression. Furthermore, the selection marker gene was efficiently removed using the Cre/loxP system. The three glycan antigens were completely absent at both cellular and tissue levels in BM7G genetically modified pigs. What's more, four protective proteins were stably expressed in vascular endothelial cells and major organs such as the heart, liver, and kidneys. Among them, hCD55 and hCD46 were widely expressed, while hTHBD and hEPCR were specifically expressed in the vascular region. In-vitro functional assays confirmed that BM7G porcine vascular endothelial cells significantly reduced the binding of human antibodies, effectively inhibited complement-dependent cytotoxicity, and decreased the formation of thrombin-antithrombin (TAT) complexes. In summary, by combining the knockout of xenoantigens with the use of endogenous promoters to drive the expression of multiple human protective genes, we successfully constructed a seven-gene modified pig model with low immunogenicity and synergistic protective functions. This provides an important donor resource for preclinical research in xenotransplantation.

Patient-derived orthotopic xenotransplantation (PDOX) models have recently emerged as a potential approach for experimental therapeutics and precision medicine in malignant disease. However, the clinical application of PDOX models was restricted by the varying success rate of the animal models, long generation time, limited number of patient tumor cells and distinct stromal environments. To address this critical barrier, we developed an innovative patient-derived cell ring organoid platform using scaffold-free tumor cell rings. By co-culturing primary sarcoma cells with human skin fibroblasts (HSFs), functional tumor microenvironment (TME) -incorporated organoids were generated within 48 h without exogenous matrices. These organoids enabled rapid establishment of orthotopic xenografts (r-PDOX) in ≤7 days with 100% engraftment efficiency while requiring 50% fewer cells than conventional methods. Crucially, integrated HSFs replicated desmoplastic stroma and vascular networks, preserving patient-specific molecular profiles (transcriptomic correlation r = 0.87) and biological processes. As a preliminary proof-of-concept, the r-PDOX models showed encouraging concordance with patient responses to first-line therapeutics, including ifosfamide and anlotinib, though validation in larger cohorts is required. This platform overcomes key limitations of existing sarcoma models - including cell leakage, phenotypic drift, and protracted timelines, offering a physiologically relevant tool for personalized therapy exploration. The platform represents a promising methodological foundation for rapid sarcoma preclinical modeling in the era of precision oncology.

Corneal blindness remains a major cause of preventable vision loss worldwide; however, the global shortage of donor corneas severely limits transplantation. Xenotransplantation using porcine corneas represents a potential solution. Here, we report the first-in-human transplantation of porcine corneal endothelial grafts. Descemet's stripping automated endothelial keratoplasty (DSAEK) was performed using pathogen-free, nongenetically modified porcine grafts in 2 patients with painful bullous keratopathy and irreversible vision loss. One patient received topical corticosteroids alone, the other systemic mycophenolate mofetil. Clinical outcomes, graft survival, immune rejection, and zoonotic safety were monitored over extended follow-up. Both grafts adhered well and restored early corneal clarity. Immune rejection occurred on days 41 and 154, with longer graft survival in the patient under systemic immunosuppression. Histologic and immunohistochemical revealed chronic inflammatory infiltration with lymphocytes and eosinophils, together with lymphocytes, eosinophils, complement, immunoglobulins, T cells, B cells, and macrophages. No zoonotic transmission was detected over 34 mo. Both patients subsequently underwent successful allogeneic corneal transplantation, resolving ocular pain. Porcine corneal endothelial grafts can temporarily restore corneal transparency and relieve symptoms in end-stage bullous keratopathy; however, immune rejection remains the principal barrier to durable survival. Absence of zoonotic infection supports initial clinical safety.

Cardiac xenotransplantation (CXTx) has emerged as a potentially transformative solution to the global shortage of donor organs, driven by recent breakthroughs in genome-editing technologies. This review provides a comprehensive overview of the field, tracing its evolution from early experimental barriers to the current stage of early clinical translation. We summarize the significant strides made in the development of genetically engineered donor pigs, in which multi-gene modifications have effectively overcome the obstacle of hyperacute rejection. Despite these advances, long-term graft survival remains limited by complex immunological and physiological challenges, including acute humoral xenograft rejection, cellular immune responses, and coagulation dysregulation. Furthermore, this review critically analyzes data from recent milestones, including studies in brain-dead decedent models and the first genetically modified pig-to-human heart transplants. These clinical endeavors have exposed critical unresolved issues, particularly antibody-mediated rejection and the biosafety risks associated with porcine viruses. In conclusion, we discuss the key pathways for future progress, emphasizing the urgent need for optimized immunosuppressive regimens, rigorous viral surveillance, and standardized preclinical protocols to establish CXTx as a safe and durable clinical reality.

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