纳米材料在脑卒中诊断及治疗中的研究进展

doi:10.3877/cma.j.issn.2095-123X.2026.03.007

脑卒中具有高致死率和高致残率，是危害人类健康的重大脑血管疾病。传统药物为其主要治疗方案，但由于血脑屏障（BBB）等因素的限制，药物的精准作用效能及安全应用水平仍有待提升。随着纳米医学的不断发展，纳米材料逐渐应用于多个医学领域，为脑卒中的诊断和治疗带来了新的研究思路。纳米材料具有尺寸效应等优势，不仅可以提高影像技术的分辨率和敏感性，实现早期病变检测，还可以穿越BBB，提高药物的靶向递送效率。目前纳米材料的临床转化仍面临生物安全性、质量控制等挑战，随着研究与技术的进步，该类技术有望突破现存问题，成为脑血管疾病治疗的重要手段。本文主要综述纳米材料在脑卒中诊疗方面的最新研究进展，并探讨其临床转化面临的困难与未来发展方向，旨在为脑卒中新型纳米诊疗策略的后续研究与临床转化提供参考。

关键词: 脑卒中, 纳米材料, 血脑屏障, 靶向递送, 诊断, 治疗

Stroke is a major cerebrovascular disease with high mortality and disability rates that seriously threaten human health. Conventional pharmacotherapy serves as the main treatment for stroke. Nevertheless, restricted by the blood brain barrier (BBB) and other obstacles, drugs fail to achieve satisfactory targeted efficacy and biosafety, leaving much room for improvement. With the rapid development of nanomedicine, nanomaterials have been widely adopted in various medical fields, offering novel research avenues for stroke diagnosis and treatment. Benefiting from unique properties including nanoscale size effects, nanomaterials can elevate the resolution and sensitivity of imaging modalities for early lesion identification, and cross the BBB to boost the efficiency of targeted drug delivery. At present, the clinical translation of nanomaterials is hampered by multiple challenges such as biosafety risks and standardized quality control. Along with sustained advances in fundamental research and manufacturing technology, nanomaterial-based platforms are expected to address current bottlenecks and emerge as critical therapeutic tools for cerebrovascular disorders. This review recapitulates cutting-edge research progress of nanomaterials in stroke theranostics, analyzes translational barriers and prospective development trends, and intends to provide references for further investigation and clinical transformation of innovative nano-theranostic strategies against stroke.

Key words: Stroke, Nanomaterials, Blood brain barrier, Targeted delivery, Diagnostic, Treatment

表1 纳米材料的分类

Tab.1 Classification of nanomaterials

分类	NPs/载体	靶向机制	治疗机制
脂质体NPs	PSL	PSL表面的PS能模拟凋亡细胞信号，靶向血肿区聚集的M/MΦ	递送IL-10后促进血肿清除，抑制M1相关神经炎症，减轻神经元损伤
	FK506-脂质体	以尺寸优化和PEG化延长循环时间实现被动靶向	抑制氧化应激和钙信号通路，减轻I/R损伤，改善神经功能
	Xe-脂质体	Xe本身不受BBB限制，依赖超声触发释放	Xe发挥抗凋亡、抗炎作用，减轻早期脑损伤，改善神经功能
靶向聚合物NPs	PLGA-PEG-CeO₂	PEG化增强稳定性、延长循环并提升BBB穿透力，属以材料修饰为主的靶向递送	CeO₂清除ROS，减轻I/R相关氧化应激，保护脑血管系统
	D&G@NPEOz	中性粒细胞膜借助炎症趋化性定向到炎症病灶；pH敏感脂质使药物在酸性微环境快速释放	GW280264X与desmosterol协同抑制炎症因子释放、调节炎症反应并促进神经修复
	C-Lipo/CA	CREKA肽识别血栓中的纤维蛋白；TK基团在高ROS环境中断裂，实现病灶响应释放	释放PAD4抑制剂Cl-amidine，抑制中性粒细胞胞外陷阱形成，减轻脑损伤
无机NPs	纤维蛋白靶向金NPs	通过纤维蛋白靶向外壳特异性结合血栓	不以直接治疗为主；而是通过CT显影监测溶栓进程，提升治疗精准性和安全性
	CeO₂ NP	主要依赖尺寸效应/被动跨BBB到达病灶	利用Ce³⁺/Ce⁴⁺价态转换清除ROS和RNS，减轻氧化应激损伤
	聚多巴胺NP	血小板膜赋予其对受损血管/出血区域的定向黏附能力	聚多巴胺本身清除ROS，并发挥抗炎作用，从而保护脑组织
	MnCO₃@BSA-ICG	在缺血酸性微环境中pH响应激活，并在病灶区特异聚集	不以直接治疗为主，而是通过MR/PA双模态成像提升对比度，动态监测脑氧状态
	羧基修饰Fe₃O₄ NP	通过表面羧基修饰提升稳定性和生物相容性	无直接治疗机制，主要增强T2加权MRI检测能力
	超顺磁性氧化铁示踪剂	主要依赖磁性成像示踪	无直接治疗机制，用于磁粒子成像实时发现出血并进行监测
	ZIF-8/CeO₂ NP	ZIF-8提供保护和酸响应释放，帮助CeO₂顺利到达病灶区	CeO₂清除ROS，ZIF-8在酸性环境分解后释放CeO₂，从而清除ROS
复合NPs	巨噬细胞膜-MnO₂-FTY	巨噬细胞膜依赖炎症趋化性将颗粒递送至炎症区域	降低氧化应激并产生O₂缓解缺氧，促进M1→M2极化，并抑制NF-κB减少促炎因子
	CeO₂-PEG-NBP	依靠PEG延长循环、提高稳定性和降低免疫原性	清除ROS、缓解氧化应激、促进血管生成、神经发生和神经可塑性，改善感觉和运动功能
	PNzyme/MnO₂	识别血栓/凝血相关微环境，并可跨BBB至病灶	实现血栓靶向溶解并清除ROS
	NTA/Ce⁴⁺/C-176 NP	对病变区域游离dsDNA的选择性	形成类DNase催化中心，水解游离dsDNA，减少cGAS-STING通路激活，缓解炎症
仿生智能NPs	TSEL	通过将外泌体包覆并与具有脑靶向功能的多肽Angiopep-2进行偶联，从而实现跨越BBB	降低β-淀粉样蛋白生成并促进小胶质细胞向抗炎表型转化，缓解神经炎症
	RGD-EV	表面RGD肽识别缺血区血管内皮高表达的整合素α_vβ₃	EVs携带miRNA抑制MAPK等炎症相关通路，减轻炎症反应

表1 纳米材料的分类

Tab.1 Classification of nanomaterials

分类	NPs/载体	靶向机制	治疗机制
脂质体NPs	PSL	PSL表面的PS能模拟凋亡细胞信号，靶向血肿区聚集的M/MΦ	递送IL-10后促进血肿清除，抑制M1相关神经炎症，减轻神经元损伤
	FK506-脂质体	以尺寸优化和PEG化延长循环时间实现被动靶向	抑制氧化应激和钙信号通路，减轻I/R损伤，改善神经功能
	Xe-脂质体	Xe本身不受BBB限制，依赖超声触发释放	Xe发挥抗凋亡、抗炎作用，减轻早期脑损伤，改善神经功能
靶向聚合物NPs	PLGA-PEG-CeO₂	PEG化增强稳定性、延长循环并提升BBB穿透力，属以材料修饰为主的靶向递送	CeO₂清除ROS，减轻I/R相关氧化应激，保护脑血管系统
	D&G@NPEOz	中性粒细胞膜借助炎症趋化性定向到炎症病灶；pH敏感脂质使药物在酸性微环境快速释放	GW280264X与desmosterol协同抑制炎症因子释放、调节炎症反应并促进神经修复
	C-Lipo/CA	CREKA肽识别血栓中的纤维蛋白；TK基团在高ROS环境中断裂，实现病灶响应释放	释放PAD4抑制剂Cl-amidine，抑制中性粒细胞胞外陷阱形成，减轻脑损伤
无机NPs	纤维蛋白靶向金NPs	通过纤维蛋白靶向外壳特异性结合血栓	不以直接治疗为主；而是通过CT显影监测溶栓进程，提升治疗精准性和安全性
	CeO₂ NP	主要依赖尺寸效应/被动跨BBB到达病灶	利用Ce³⁺/Ce⁴⁺价态转换清除ROS和RNS，减轻氧化应激损伤
	聚多巴胺NP	血小板膜赋予其对受损血管/出血区域的定向黏附能力	聚多巴胺本身清除ROS，并发挥抗炎作用，从而保护脑组织
	MnCO₃@BSA-ICG	在缺血酸性微环境中pH响应激活，并在病灶区特异聚集	不以直接治疗为主，而是通过MR/PA双模态成像提升对比度，动态监测脑氧状态
	羧基修饰Fe₃O₄ NP	通过表面羧基修饰提升稳定性和生物相容性	无直接治疗机制，主要增强T2加权MRI检测能力
	超顺磁性氧化铁示踪剂	主要依赖磁性成像示踪	无直接治疗机制，用于磁粒子成像实时发现出血并进行监测
	ZIF-8/CeO₂ NP	ZIF-8提供保护和酸响应释放，帮助CeO₂顺利到达病灶区	CeO₂清除ROS，ZIF-8在酸性环境分解后释放CeO₂，从而清除ROS
复合NPs	巨噬细胞膜-MnO₂-FTY	巨噬细胞膜依赖炎症趋化性将颗粒递送至炎症区域	降低氧化应激并产生O₂缓解缺氧，促进M1→M2极化，并抑制NF-κB减少促炎因子
	CeO₂-PEG-NBP	依靠PEG延长循环、提高稳定性和降低免疫原性	清除ROS、缓解氧化应激、促进血管生成、神经发生和神经可塑性，改善感觉和运动功能
	PNzyme/MnO₂	识别血栓/凝血相关微环境，并可跨BBB至病灶	实现血栓靶向溶解并清除ROS
	NTA/Ce⁴⁺/C-176 NP	对病变区域游离dsDNA的选择性	形成类DNase催化中心，水解游离dsDNA，减少cGAS-STING通路激活，缓解炎症
仿生智能NPs	TSEL	通过将外泌体包覆并与具有脑靶向功能的多肽Angiopep-2进行偶联，从而实现跨越BBB	降低β-淀粉样蛋白生成并促进小胶质细胞向抗炎表型转化，缓解神经炎症
	RGD-EV	表面RGD肽识别缺血区血管内皮高表达的整合素α_vβ₃	EVs携带miRNA抑制MAPK等炎症相关通路，减轻炎症反应

[1]	Sharma R, Lee K. Advances in treatments for acute ischemic stroke[J]. BMJ, 2025, 389: e076161. DOI: 10.1136/bmj-2023-076161.
[2]	Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders[J]. Nat Rev Neurosci, 2011, 12(12): 723-738. DOI: 10.1038/nrn3114.
[3]	Kristián T. Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage[J]. Cell Calcium, 2004, 36(3-4): 221-233. DOI: 10.1016/j.ceca.2004.02.016.
[4]	苗楠，宗子钰. 脑出血后继发性脑损伤与线粒体相关机制的研究进展[J]. 中华神经创伤外科电子杂志, 2024, 10(2): 107-111. DOI: 10.3877/cma.j.issn.2095-9141.2024.02.008.
[5]	Chamorro Á, Meisel A, Planas AM, et al. The immunology of acute stroke[J]. Nat Rev Neurol, 2012, 8(7): 401-410. DOI: 10.1038/nrneurol.2012.98.
[6]	Lan X, Han X, Li Q, et al. Modulators of microglial activation and polarization after intracerebral haemorrhage[J]. Nat Rev Neurol, 2017, 13(7): 420-433. DOI: 10.1038/nrneurol.2017.69.
[7]	Gao J, Xia Z, Gunasekar S, et al. Precision drug delivery to the central nervous system using engineered nanoparticles[J]. Nature Reviews Materials, 2024, 9(8): 567-588. DOI: 10.1038/s41578-024-00695-w.
[8]	张传鹏，张瑜廉，党韩寒，等. 胶质母细胞瘤免疫治疗挑战与cGAS-STING通路纳米策略研究进展[J]. 中华脑科疾病与康复杂志(电子版), 2025, 15(3): 153-160. DOI: 10.3877/cma.j.issn.2095-123X.2025.03.004.
[9]	Turkmen Koc SN, Rezaei Benam S, Aral IP, et al. Gold nanoparticles-mediated photothermal and photodynamic therapies for cancer[J]. Int J Pharm, 2024, 655: 124057. DOI: 10.1016/j.ijpharm.2024.124057.
[10]	Bruna T, Maldonado-Bravo F, Jara P, et al. Silver nanoparticles and their antibacterial applications[J]. Int J Mol Sci, 2021, 22(13): 7202. DOI: 10.3390/ijms22137202.
[11]	Conde J, Langer R, Rueff J. mRNA therapy at the convergence of genetics and nanomedicine[J]. Nature Nanotechnology, 2023, 18(6): 537-540. DOI: 10.1038/s41565-023-01347-w.
[12]	Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases[J]. J Control Release, 2017, 264: 306-332. DOI: 10.1016/j.jconrel.2017.08.033.
[13]	Gao Y, Chen X, Liu H. A facile approach for synthesis of nano-CeO2 particles loaded co-polymer matrix and their colossal role for blood-brain barrier permeability in cerebral ischemia[J]. J Photochem Photobiol B, 2018, 187: 184-189. DOI: 10.1016/j.jphotobiol.2018.05.003.
[14]	Muller AP, Ferreira GK, Pires AJ, et al. Gold nanoparticles prevent cognitive deficits, oxidative stress and inflammation in a rat model of sporadic dementia of Alzheimer's typea[J]. Mater Sci Eng C Mater Biol Appl, 2017, 77: 476-483. DOI: 10.1016/j.msec.2017.03.283.
[15]	Wang Z, Zhao Y, Hou Y, et al. A Thrombin-activated peptide-templated nanozyme for remedying ischemic stroke via thrombolytic and neuroprotective actions[J]. Adv Mater, 2024, 36(10): e2210144. DOI: 10.1002/adma.202210144.
[16]	Jiang S, Cai G, Yang Z, et al. Biomimetic nanovesicles as a dual gene delivery system for the synergistic gene therapy of Alzheimer's disease[J]. ACS Nano, 2024, 18(18): 11753-11768. DOI: 10.1021/acsnano.3c13150.
[17]	Tian T, Cao L, He C, et al. Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia[J]. Theranostics, 2021, 11(13): 6507-6521. DOI: 10.7150/thno.56367.
[18]	Barick KC, Singh S, Bahadur D, et al. Carboxyl decorated Fe3O4 nanoparticles for MRI diagnosis and localized hyperthermia[J]. J Colloid Interface Sci, 2014, 418: 120-125. DOI: 10.1016/j.jcis.2013.11.076.
[19]	Song G, Zhang B, Song L, et al. MnCO₃@BSA-ICG nanoparticles as a magnetic resonance/photoacoustic dual-modal contrast agent for functional imaging of acute ischemic stroke[J]. Biochem Biophys Res Commun, 2022, 614: 125-131. DOI: 10.1016/j.bbrc.2022.04.143.
[20]	Szwargulski P, Wilmes M, Javidi E, et al. Monitoring intracranial cerebral hemorrhage using multicontrast real-time magnetic particle imaging[J]. ACS Nano, 2020, 14(10): 13913-13923. DOI: 10.1021/acsnano.0c06326.
[21]	National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke[J]. N Engl J Med, 1995, 14, 333(24): 1581-1588. DOI: 10.1056/NEJM199512143332401.
[22]	Kirmani JF, Alkawi A, Panezai S, et al. Advances in thrombolytics for treatment of acute ischemic stroke[J]. Neurology, 2012, 79(13 Suppl 1): S119-S125. DOI: 10.1212/WNL.0b013e3182695882.
[23]	Kim JY, Ryu JH, Schellingerhout D, et al. Direct imaging of cerebral thromboemboli using computed tomography and fibrin-targeted gold nanoparticles[J]. Theranostics, 2015, 5(10): 1098-1114. DOI: 10.7150/thno.11679.
[24]	Fan L, Jin L, Tang T, et al. Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage[J]. Theranostics, 2024, 14(1): 283-303. DOI: 10.7150/thno.90370.
[25]	Han R, Lan X, Han Z, et al. Improving outcomes in intracerebral hemorrhage through microglia/macrophage-targeted IL-10 delivery with phosphatidylserine liposomes[J]. Biomaterials, 2023, 301: 122277. DOI: 10.1016/j.biomaterials.2023.122277.
[26]	Sun S, Lv W, Li S, et al. Smart Liposomal nanocarrier enhanced the treatment of ischemic stroke through neutrophil extracellular traps and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway inhibition of ischemic penumbra[J]. ACS Nano, 2023, 17(18): 17845-17857. DOI: 10.1021/acsnano.3c03390.
[27]	He L, Huang G, Liu H, et al. Highly bioactive zeolitic imidazolate framework-8-capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke[J]. Sci Adv, 2020, 6(12): eaay9751. DOI: 10.1126/sciadv.aay9751.
[28]	Takahashi A, Loo TM, Okada R, et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells[J]. Nat Commun, 2018, 9(1): 1249. DOI: 10.1038/s41467-018-03555-8.
[29]	Zhu Z, Lu H, Jin L, et al. C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment[J]. Bioact Mater, 2023, 29: 230-240. DOI: 10.1016/j.bioactmat.2023.07.002.
[30]	Li C, Zhao Z, Luo Y, et al. Macrophage‐disguised manganese dioxide nanoparticles for neuroprotection by reducing oxidative stress and modulating inflammatory microenvironment in acute ischemic stroke[J]. Adv Sci (Weinh), 2021, 8(20): e2101526. DOI: 10.1002/advs.202101526.
[31]	Li X, Han Z, Wang T, et al. Cerium oxide nanoparticles with antioxidative neurorestoration for ischemic stroke[J]. Biomaterials, 2022, 291: 121904. DOI: 10.1016/j.biomaterials.2022.121904.
[32]	Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review[J]. Adv Drug Deliv Rev, 2002, 54(4): 531-545. DOI: 10.1016/s0169-409x(02)00026-1.
[33]	Lovelock CE, Rinkel G JE, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review[J]. Neurology, 2010, 74(19): 1494-1501. DOI: 10.1212/WNL.0b013e3181dd42b3.
[34]	Xu P, Liu Y, Wang J, et al. Gender-specific prognosis models reveal differences in subarachnoid hemorrhage patients between sexes[J]. CNS Neurosci Ther, 2024, 30(8): e14894. DOI: 10.1111/cns.14894.
[35]	Zawadzka M, Dabrowski M, Gozdz A, et al. Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke[J]. J Mol Med (Berl), 2012, 90(12): 1459-1471. DOI: 10.1007/s00109-012-0925-9.
[36]	Fukuta T, Ishii T, Asai T, et al. Treatment of stroke with liposomal neuroprotective agents under cerebral ischemia conditions[J]. Eur J Pharm Biopharm, 2015, 97(Pt A): 1-7. DOI: 10.1016/j.ejpb.2015.09.020.
[37]	Homi HM, Yokoo N, Ma D, et al. The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice[J]. Anesthesiology, 2003, 99(4): 876-881. DOI: 10.1097/00000542-200310000-00020.
[38]	Miao YF, Peng T, Moody MR, et al. Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage[J]. Sci Rep, 2018, 8(1): 450. DOI: 10.1038/s41598-017-18914-6.
[39]	Najahi-Missaoui W, Arnold RD, Cummings BS. Safe nanoparticles: are we there yet?[J]. Int J Mol Sci, 2020, 22(1): 385. DOI: 10.3390/ijms22010385.

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Advances in nanomaterial-driven diagnostic and therapeutic strategies for stroke

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Advances in nanomaterial-driven diagnostic and therapeutic strategies for stroke