Nanoparticle delivery of CD40 siRNA suppresses alloimmune responses by inhibiting activation and differentiation of DCs and macrophages

Jialiang Wang; Kuirong Mao; Xiuxiu Cong; Huizhu Tan; Chenxi Wu; Zheng Hu; Yong-Guang Yang; Tianmeng Sun

doi:10.1126/sciadv.abq3699

Nanoparticle delivery of CD40 siRNA suppresses alloimmune responses by inhibiting activation and differentiation of DCs and macrophages

Sci Adv. 2022 Dec 21;8(51):eabq3699. doi: 10.1126/sciadv.abq3699. Epub 2022 Dec 21.

Authors

Jialiang Wang^{1

2}, Kuirong Mao^{1

2

3}, Xiuxiu Cong^{1

2}, Huizhu Tan^{1

2}, Chenxi Wu¹, Zheng Hu^{1

2}, Yong-Guang Yang^{1

2

3}, Tianmeng Sun^{1

2

3

4}

Affiliations

¹ Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China.
² National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China.
³ International Center of Future Science, Jilin University, Changchun, Jilin, China.
⁴ State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin, China.

Abstract

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 (siCD40/NPs) to effectively deliver CD40 siRNA (siCD40) into hematopoietic stem cells (HSCs), myeloid progenitors, and mature dendritic cells (DCs) and macrophages. Injection of siCD40/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, siCD40/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 siCD40/NPs in suppressing alloimmune responses, providing a potential means of facilitating tolerance induction and preventing allotransplant rejection.