From transient gene-transferred porcine skin to multigene-edited xenografts: Translational evolution of xenogeneic skin transplantation

Extensive burns and complex acute or chronic wounds continue to expose a persistent mismatch between the demand for biological wound coverage and the limited availability of autologous and allogeneic skin. Porcine skin is structurally similar to human skin and can be produced at scale, but its clinical use has historically been constrained by immune rejection and biosafety concerns. This review summarizes the translational evolution of xenogeneic skin transplantation from conventional porcine dressings to engineered living xenografts, with special emphasis on a three-generation development pathway: ex vivo CTLA4Ig gene-transferred porcine skin, skin-specific hCTLA4Ig transgenic porcine skin, and multigene-edited porcine skin designed to modulate carbohydrate antigens, complement activation, T-cell costimulation, coagulation, and pathogen risk. The first-generation CTLA4Ig gene-transferred porcine skin has been registered and clinically used in China as a Class III medical device for temporary wound coverage, in which transient local expression of CTLA4Ig delays rejection without systemic immunosuppression. The second generation seeks to replace ex vivo transient modification with stable skin-specific expression, improving consistency and extending the functional window of coverage. The third generation integrates glycan-antigen deletion, complement regulation and high-affinity costimulation blockade, including LEA29Y, to address the multilayered biology of xenogeneic rejection. We further discuss international clinical translation of genetically engineered porcine skin, manufacturing and regulatory considerations, and future directions in functionalized xenograft skin for infection control, scar modulation, vascularization and broader wound indications. Engineered porcine skin is unlikely to replace autologous grafting in all settings, but it can become a scalable, living, immunologically tuned bridge between emergency wound closure and definitive tissue reconstruction.