Photoresponsive Vaccine-Like CAR-M System with High-Efficiency Central Immune Regulation for Inflammation-Related Depression
Photoresponsive Vaccine-Like CAR-M System with High-Efficiency Central Immune Regulation for Inflammation-Related Depression
复制标题
具有高效中枢免疫调节功能的光响应类疫苗 CAR-M 系统，用于治疗炎症相关抑郁症
DOI：
10.1002/adma.202108525
复制
发表时间：
2022-02-06
影响因子：
29.4
通讯作者：
Wang, Xiaolei
中科院分区：
文献类型：
--
作者：
Liu, Yu;Hu, Ping;Wang, Xiaolei
越来越多的证据表明，激活小胶质细胞诱导的神经炎症在抑郁症的病理生理中起着至关重要的作用。因此，以中枢神经系统为目标，减少神经炎症，对治疗抑郁症有很大的希望。然而，很少有药物能够通过血脑屏障（BBB）的循环途径进入大脑，有效地到达中枢神经系统，这限制了神经精神疾病的药物治疗。为了解决上述问题，本文开发了一种名为UZPM的光响应系统，该系统由蓝色发射的NaYF4:Yb， Tm@zeolitic-imidazolate框架（UCNP@ZIF-8），光酸（PA）和褪黑激素（MT）组成。同时，通过功能性脂质体融合将UZPM引入巨噬细胞，并在细胞表面与羟胺基团修饰。醛修饰的细胞毒性t淋巴细胞相关蛋白-4 （CTLA-4）作为嵌合抗原受体（CAR）靶向基团，通过醛/羟胺凝聚修饰巨噬细胞表面，精确靶向中央m1型小胶质细胞（CAR- m - uzpm）。体外和体内实验均表明，CAR-M-UZPM给药系统能有效穿透血脑屏障，靶向中枢活化的小胶质细胞，从而抑制小胶质细胞的m1型极化，产生持续的疫苗样抗炎作用，防止炎症相关性抑郁的发生和发展。
Increasing evidence suggests that activation of microglia-induced neuroinflammation plays a crucial role in the pathophysiology of depression. Consequently, targeting the central nervous system to reduce neuroinflammation holds great promise for the treatment of depression. However, few drugs can enter the brain via a circulatory route through the blood-brain barrier (BBB) to reach the central nervous system efficiently, which limits the pharmacological treatment for neuropsychiatric diseases. Herein, a light-responsive system named UZPM, consisting of blue-emitting NaYF4:Yb, Tm@zeolitic-imidazolate framework (UCNP@ZIF-8), photoacid (PA), and melatonin (MT) is developed to address the above issues. Meanwhile, UZPM is introduced into macrophages by functional liposomes fusion and modified with hydroxylamine groups on the cell surface. Aldehyde-modified cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is used as a chimeric antigen receptor (CAR) targeting group to modify the surface of macrophages by aldehyde/hydroxylamine condensation to precisely target central M1-type microglia (CAR-M-UZPM). Both in vitro and in vivo experiments demonstrate that the CAR-M-UZPM drug delivery system can efficiently penetrate the BBB, targeting centrally activated microglia, and thus, inhibiting the M1-type polarization of microglia, producing continuous vaccine-like anti-inflammatory effects that prevent the occurrence and development of inflammation-related depression.