Graphene oxide-based plasma membrane-philic delivery platform to generate tolerogenic dendritic cells in GVHD immunotherapy

The prevention and treatment of graft-versus-host disease (GVHD) remain a barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Tolerogenic dendritic cells (TDCs) have become a hotspot for GVHD prevention, despite their poor induction efficiency. In this study, we designed a novel size-dependent platform of graphene oxide (GO) nanosheets for neuropeptide delivery for TDC generation. GO nanosheets with a lateral size> 1 µm (L-GO) showed strong affinity to the DC membrane, which effectively promoted the recognition of neuropeptides, urocortin (UCN), and its receptor CRHR2, and in turn benefited TDC generation through PKA-C/CREB phosphorylation. Simultaneously, L-GO elevated the expression of CCR7 and enhanced the migration ability of TDCs by mediating cytoskeletal reorganization. In vivo experiments offered direct evidence that TDCs induced by UCN@L-GO exhibited efficient migration to lymph nodes (LNs), abundant generation of Tregs, a significant decrease in proinflammatory cytokines, and excellent efficiency in GVHD relief. In this study, we propose an innovative GO nanosheet-based cytomembrane-targeted platform for neuropeptide delivery and subsequent TDC generation. Meanwhile, the enhanced mobility of TDC pulsed by GO nanosheets ensured high homing efficiency to secondary lymph nodes, which was attributed to GVHD treatment in vivo. Thus, this work provides a promising strategy that might be applicable more broadly to delivery systems for receptor-mediated drugs and could meet the changing demand of nanotechnology-based immunotherapy. [Display omitted] •Large-sized graphene oxide (L-GO) nanosheets were selected as a novel plasma membrane-phillic delivery platform.•L-GOs facilitated the recognition between neuropeptide and its receptor to induce tolerogenic DCs.•L-GOs promoted DCs’ mobility through cytoskeleton rearrangement even under the tolerant phenotype.•TDCs generated by UCN@L-GO remarkably regulated the phenotype of donor T cells and protected recipients from lethal GVHD.