Nanotechnology-Driven Precision Modulation of Transplant Immunity: From Mechanistic Insights to Clinical Tolerance

Organ transplantation represents a definitive therapeutic modality for end-stage organ failure, yet it is plagued by formidable challenges encompassing allogeneic immune rejection and the inherent limitations of conventional immunosuppressive regimens. Nonspecific immunosuppression not only precipitates severe adverse events such as opportunistic infections and malignancies but also fails to precisely modulate the local immune microenvironment. The core innovation of this review lies in the systematic integration of the distinctive advantages of nanotechnology-including targeted delivery, multifunctional synergy, and stimuli-responsive intelligence-with transplant immune regulation, encompassing a comprehensive analysis spanning mechanistic elucidation, strategic optimization, and clinical translation. We first delineate the pivotal mechanisms underlying immune rejection, including the regulatory roles of the transplant immune microenvironment, T lymphocytes, macrophages, and oxidative stress in ischemia-reperfusion injury (IRI). Subsequently, we conduct a critical comparison between conventional immunosuppressants and emerging therapeutic strategies, with a particular focus on how nanoplatforms enable spatiotemporally precise immune modulation. This includes targeting the transplant immune microenvironment, reprogramming T cell/macrophage functions, mitigating oxidative stress, facilitating tissue repair and regeneration, as well as inducing immune tolerance via both active and passive approaches. Additionally, we discuss innovative nanotechnological strategies such as the optimization of organ cryopreservation protocols. In summary, nanotechnology offers a targeted, multifunctional, and long-acting paradigm for transplant immune regulation, albeit confronted with formidable translational bottlenecks. Future integration with interdisciplinary technologies will undoubtedly propel the field toward the goal of precision immune modulation in organ transplantation.