PD-L1 cellular nanovesicles carrying rapamycin inhibit alloimmune responses in transplantation†
‡a
Zhanxue
Xu,
‡a
Hailan
Yan,
‡a
Hsiang-i
Tsai,
a
Dandan
Su,
a
Fuxia
Yan,
a
Qiumei
Lu,
a
Jianhua
Feng,
b
Weiwei
Zeng,
a
Lifang
Xi,
a
Hualian
Zha,
a
Yunzhi
Ling,
a
Chao
He,
a
Yingyi
Wu,
a
Xiaowei
Xu,
c
Gang
Zheng,
d
Gan
Liu,
*a
Hongbo
Chen
*a
and
Fang
Cheng
*a
Abstract
Organ transplantation has been employed upon serious injuries, but a T-cell-mediated potent inflammatory immune response often leads to graft rejection. Immunosuppressive drugs such as rapamycin (RAPA) have to be taken after organ transplantation, but long-term use of these drugs causes severe adverse effects. Immune checkpoint pathways such as the programmed death-receptor 1/programmed death-ligand 1 (PD-1/PD-L1) provides an immunosuppressive environment, preventing excessive tissue destruction due to inflammatory immune responses. In this study, we bioengineered cell membrane-derived PD-L1 nanovesicles (PD-L1 NVs) to carry low doses of RAPA. These NVs inhibited T-cell activation and proliferation in vitro, by enhancing the PD-1/PD-L1 immune co-inhibitory signaling axis and inhibiting the mTOR pathway. Importantly, PD-L1 NVs encapsulated with rapamycin exerted stronger effects on inhibiting T-cell proliferation than PD-L1 NVs or rapamycin alone. This can be recapitulated in a mouse skin transplantation model, leading to the weakened alloimmune response and allograft tolerance. We also found that PD-L1/rapamycin vesicles have additional function to induce regulatory T cells in the recipient spleens. Our study highlighted the power of combining low-dose rapamycin and PD-L1 in the nanovesicles as immunosuppressants to promote allograft acceptance.
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