CD40
is an important costimulatory molecule expressed on antigen-presenting cells (APCs) and plays a critical role for APC activation, offering a promising therapeutic target for preventing allograft rejection. Here, we developed a biodegradable nanoparticle small interfering RNA delivery system (si
CD40
/NPs) to effectively deliver
CD40
siRNA (si
CD40
) into hematopoietic stem cells (HSCs), myeloid progenitors, and mature dendritic cells (DCs) and macrophages. Injection of si
CD40
/NPs not only down-regulated
CD40
expression in DCs and macrophages but also inhibited the differentiation of HSCs and/or myeloid progenitors into functional DCs and macrophages. Furthermore, si
CD40
/NPs treatment significantly prolonged allograft survival in mouse models of skin allotransplantation. In addition to reiteration of the role of
CD40
in APC activation, our findings highlight a previously unappreciated role of
CD40
in DC and macrophage differentiation from their progenitors. Furthermore, our results support the effectiveness of si
CD40
/NPs in suppressing alloimmune responses, providing a potential means of facilitating tolerance induction and preventing allotransplant rejection.
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