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.
Jialiang Wang  1  2 ,  Kuirong Mao  1  2  3 ,  Xiuxiu Cong  1  2 ,  Huizhu Tan  1  2 ,  Chenxi Wu  1 ,  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.
PMID: 36542700 DOI: 10.1126/sciadv.abq3699
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.

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