针对我国缺血性脑卒中病人入院时间滞后、溶栓治疗难以实施的普遍现状，本项目拟构建一类抑制脑缺血次急性期“炎性反应”的跨血脑屏障（BBB）纳米激动剂（NA）实现神经保护疗效。该NA由氧化铈核心（CeNP）和标记有腺苷A2A受体（A2AR）激动基团、靶向基团和影像基团的自组装胶束涂层构成。NA首先靶向脑缺血组织血管，激活内皮细胞A2AR开启BBB，入脑后激活神经/淋巴样细胞A2AR抑制缺血“炎性反应”，并通过CeNP拟酶效应消除炎症过程中产生的活性氧自由基。通过磁共振和单光子发射计算机断层成像实时监测“BBB通透性”、“NA靶向入脑效率”和“神经纤维束损伤恢复”关键事件，指导NA粒径及靶向、激动基团标记数目优化，在实现神经保护疗效最大化同时降低BBB无序开启和A2AR过度激活造成副作用。该影像指导纳米激动剂功能优化策略对提高缺血性脑卒中神经保护治疗疗效，促进神经保护药物临床转化均具有重要意义。

Due to the delayed admission time, most of ischemic stroke patients in China missed the time-window for thrombolytic therapy. This project aims to develop a BBB permeable nanoagonist (NA) to improve the neuroprotective effect by blocking the “inflammatory response” that usually happens in the later stage of ischemia cascade. This NA is made up of the cerium oxide nanoparticle core (CeNP) and micellar coating that is self-assembled by amphiphilic monomers functionalized with adenosine A2A receptor (A2AR) agonist, ischemia targeting ligand and imaging reporter. NA first targets brain vessels in ischemic territories, up-regulates local BBB permeability via activation of endothelial A2AR, and finally inhibits inflammatory responses by activating A2AR expressed in neurons, astrocytes and lymphoid cells. Meanwhile, due to the enzymatic mimicking property of the CeNP core, this NP could efficiently eliminate the harmful reactive oxygen species over-produced in ischemic cascade evens. By non-invasively evaluating “BBB permeability”, “brain uptake of NA” and “nerve fiber bundle density and axonal remodeling” with magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT), it is possible to maximize the therapeutic efficacy and minimize the side-effects induced from non-specific BBB opening and A2AR over-signaling by fine tuning the particle size and the number of functional group labeled on the NA. Overall, this image-guided nanoagonist optimization strategy holds the promise of improving the therapeutic effect of ischemic stroke and accelerating the clinical translation of neuroprotecant candidates.