Targeted Expansion of Treg Cells to Induce Immune Tolerance after Kidney Transplantation

Abstract Kidney transplantation remains the optimal treatment for end‐stage renal disease, yet faces persistent challenges including organ shortages and risk of infection due to systemic immunosuppression. Cell therapy is expected to replace immunosuppressive agents. However, while Treg cell therapy can mitigate immune rejection, it fails to significantly prolong graft survival because peripherally induced Treg cells exhibit transdifferentiation potential in the circulatory system. Recent advances in nanocarrier systems offer promising approaches for achieving graft‐specific immune tolerance. Through single‐cell sequencing analysis, CD248 is identified as a pivotal stromal cell marker in renal allograft rejection, modulated by HIF‐1α and IL‐1β signaling pathways. Leveraging macrophage membrane coating technology, nanoparticles co‐loaded is developed with IL‐2 and TGF‐β expressing plasmids. These nanoparticles incorporate a CD248‐targeting antibody (IgG78) and plasmids containing a kidney‐specific NPHS2 promoter, enabling dual‐targeting capability for localized gene expression. In vitro validation demonstrated efficient differentiation of CD4⁺T cells into functional Treg populations. In rat renal transplantation models, nanoparticle treatment increased Treg cells in the graft and significantly prolonged allograft survival, improved renal function, and attenuated complement deposition. The findings establish a targeted nanoparticle platform that promotes graft‐specific immune tolerance through localized Treg cell expansion, potentially reducing dependence on systemic immunosuppression.