Targeting L-Selectin Lymphocytes to Deliver Immunosuppressive Drug in Lymph Nodes for Durable Multiple Sclerosis Treatment.
Targeting L-Selectin Lymphocytes to Deliver Immunosuppressive Drug in Lymph Nodes for Durable Multiple Sclerosis Treatment.
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DOI：
10.1002/advs.202300738
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发表时间：
2023-07
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自身反应性CD 4 + T淋巴细胞诱导的炎症反应是多发性硬化（MS）发病的主要因素。随后开发了免疫抑制药物，如FTY 720，以防止CD 4 + T淋巴细胞迁移到中枢神经系统（CNS）。然而，这些免疫抑制药物在淋巴结（LN）中的蓄积有限，导致疗效差。在这里，这项工作开发了一种纳米平台，用于将免疫抑制药物输送到LN，以进行持久的MS治疗。人CD 47肽和L-选择素靶向适体在用FTY 720（clnFTY）包封的纳米颗粒上进行修饰，用于自钝化和L-选择素在淋巴细胞上的靶向，淋巴细胞是T细胞进入LN的归巢受体。使用这种自然过程，clnFTY纳米颗粒有效地将FTY 720递送到LN，并在42天的观察期内单剂量治疗后延迟实验性自身免疫性脑脊髓炎（EAE）小鼠的疾病进展。考虑到FTY 720的每日给药需求，该策略大大提高了其治疗效率。clnFTY纳米颗粒靶向淋巴细胞、减少鞘氨醇-1-磷酸受体1（S1 PR 1）表达和抑制炎性细胞因子释放的能力在来自MS患者的临床血液样品中得到证实。总之，本研究表明，靶向LN递送可以大大延长免疫抑制药物的治疗周期，以实现持久的MS治疗。脂质体通过在脂质膜中自组装并修饰L-选择素靶向适体以靶向表达L-选择素的淋巴细胞用于淋巴结（LN）递送来用于递送FTY 720。由于FTY 720在LN中的有效递送，纳米药物有效地抑制中枢神经系统（CNS）中的淋巴细胞浸润并减轻实验性自身免疫性脑脊髓炎（EAE）小鼠的损伤。
Inflammation induced by autoreactive CD4+ T lymphocytes is a major factor in the pathogenesis of multiple sclerosis (MS). Immunosuppressive drugs, such as FTY720, are subsequently developed to prevent the migration of CD4+ T lymphocytes to the central nervous system (CNS). However, these immunosuppressive drugs have limited accumulation in lymph nodes (LNs), resulting in poor efficacy. Here, this work develops a nanoplatform for delivering immunosuppressive drugs to LNs for durable MS treatment. Human CD47 peptide and L‐selectin targeting aptamer are modified on the nanoparticles encapsulated with FTY720 (clnFTY) for self‐passivation and the targeting of L‐selectin on lymphocytes, a homing receptor for T‐cells entering LNs. Using this natural process, clnFTY nanoparticles efficiently deliver FTY720 to LNs and delay disease progression in experimental autoimmune encephalomyelitis (EAE) mice following a single dose treatment over a 42‐day observational period. Considering the daily dosing requirement of FTY720, this strategy greatly improves its therapeutic efficiency. The ability of clnFTY nanoparticles to target lymphocytes, reduce sphingosine‐1‐phosphate receptor 1 (S1PR1) expression, and suppress inflammatory cytokines release are demonstrated in clinical blood samples from MS patients. Taken together, this study demonstrates that targeted LNs delivery may greatly extend the treatment cycle of immunosuppressive drugs for durable MS treatment. Liposomes are used to deliver FTY720 by self‐assembling them in lipid membranes and decorating L‐selectin targeting aptamers to target L‐selectin expressing lymphocytes for lymph nodes (LNs) delivery. Owing to efficient delivery of FTY720 in LNs, nanodrugs efficiently inhibit lymphocytes infiltration in central nervous system (CNS) and alleviate injury in the experimental autoimmune encephalomyelitis (EAE) mice.
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影响因子：
64.8
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
影响因子：
7.3
作者：
Matsuoka, Y;Nagahara, Y;Shinomiya, T
通讯作者：
Shinomiya, T
影响因子：
25
作者：
Dong, Yifei;D'Mello, Charlotte;Yong, V. Wee
通讯作者：
Yong, V. Wee
影响因子：
32.4
作者：
Morrissey, Meghan A.;Kern, Nadja;Vale, Ronald D.
通讯作者：
Vale, Ronald D.
影响因子：
4.4
作者：
Muraro, PA;Pette, M;Martin, R
通讯作者：
Martin, R