Injectable Genetic Engineering Hydrogel for Promoting Spatial Tolerance of Transplanted Kidney in Situ

The establishment of a tolerant space to realize the co-stimulation of cytokines and contact-dependent molecules remain challenging in allotransplant. Here, an injectable genetically engineered hydrogel (iGE-Gel) is reported, which developed with a multivalent network of FOXP3 engineered extracellular vesicles (Foe-EVs) through the hydrophobic interaction between stearic acid modified hyaluronic acid (HASA) and the membrane phospholipids of extracellular vesicles (EVs). The iGE-Gel exhibited self-healing properties, injectability and biocompatibility. It is revealed that iGE-Gel displayed with abundant regulatory cytokines and coinhibitory contact molecules, promoting the formation of immune tolerance in situ. The multiplex immunohistofluorescence confirmed tolerant niches is dominated by FOXP3⁺ Tregs and PDL1⁺ cells in the allograft, which reduced the drainage of alloantigens to subcapsular sinus of lymph nodes, and suppressed the formation of germinal centers. Remarkably, the proportion of alloreactive T cells (IFN-γ/IL-2) and B cells (IgG1/IgG2a/IgG3) as well as the serum titers of donor specific antibody (DSA) is decreased by iGE-Gel. In murine allogeneic transplantation, the injection of iGE-Gel significantly alleviated immune cell infiltration and complement damage in the graft, preserved the structure and function of renal cells and prolonged recipient survival period from 30.8 to 79.3 days, highlighting the potential of iGE-Gel as a transformative treatment in allotransplant.