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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Chinese Journal of Alzheimer's Disease and Related Disorders >

2024 , Vol. 7 >Issue 2: 151 - 155

DOI: https://doi.org/10.3969/j.issn.2096-5516.2024.02.012

Review

Potential neurotoxicity of silica nanoparticles: implications for neurodegenerative diseases

  • Kexin HE , 1 ,
  • Ling GUO , 2
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  • 1 School of Pharmacy and Chemistry, Dali University, Dali 671000, Yunnan, China
  • 2 The 1st People's Hospital of Anning, Anning 650302, Kunming, China

Received date: 2024-01-25

  Revised date: 2025-03-01

  Online published: 2024-04-26

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Abstract

Neurodegenerative diseases, or Neurodegenerative-related diseases (NRDs), is a kind of chronic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD). The common path- physiological characteristics of these diseases are including abnormal protein accumulation in the neurons, oxidative stress or mitochondrial dysfunction, which result in possible neuronal death. So far there have been none of cure in the therapitic methods to these diseases. However, there are some strategies of treatments can help to relieve symptoms or delay the progression of these diseases. Silica nanoparticles (SiNPs) is a new type of material, as a drug carrier in the medical field or a neuroprotective agent in neuroscience. However, recent studies have shown that it may have negative effects on neurodegenerative diseases. It is necessary that the biosafety of SiNPs on nervous system and its working mechanisms will be further studied. Therefore, to provide a theoretical or practical guidance to people, based on the recent literatures, a review summarizes some relevent preclinical studies on SiNPs applications and its effects on neuroinflammation, mitochondrial dysfunction, Aβ and p-Tau, will be reported here by us.

Key words： Silica nanoparticles; Neurodegenerative diseases; Neuroinflammation; Mitochondrial dysfunction

Cite this article

Kexin HE , Ling GUO . Potential neurotoxicity of silica nanoparticles: implications for neurodegenerative diseases[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2024 , 7(2) : 151 -155 . DOI: 10.3969/j.issn.2096-5516.2024.02.012

世界范围内，人类面临着神经变性疾病（neurodegenerative-related diseases, NRDs）的巨大经济和社会负担。存在着衰老、家族遗传、神经炎性反应和环境因素等非常多且复杂的致病因素,具体发病机制尚未完全明晰。血脑屏障（blood-brain barrier, BBB）的存在能有效地保护大脑免受循环中潜在有害物质的侵害，但也限制了药物和较大生物分子等进入大脑。因此在NRDs相关治疗药物研发与应用中，若想实现针对脑内靶标的有效治疗或研究，必须攻克提升BBB通过率并抵达脑内靶标有效率的难题。截至目前，SiNPs广泛应用于晶石、工业材料、医药、食品和日用品等行业中，尤其是作为纳米颗粒药物递送系统（drug delivery system, DDS）的载体材料，通过不同制备工艺实现对纳米级粒径的精确控制和改善其药物包封率来实现对药物的靶向释放，尽管具有较好的生物相容性和化学稳定性，但未搭载其他药物SiNPs的研究中显示出一定的神经毒性。另外，SiNPs作为一种常见的空气污染物，通常源自工业排放、交通尾气以及煤炭或麦秆燃烧等过程[1]，释放大量可吸入颗粒污染物包括二氧化硅纳米颗粒。因此，SiNPs具有持续性的全身或局部暴露的潜在风险。本文旨在回顾近年关于SiNPs对于中枢神经系统（central nervous system, CNS）和NRDs相关的研究，重点探讨SiNPs潜在的神经毒性与神经变性疾病的关联与机制。

1 SiNPs潜在的神经毒性

神经毒性是指接触天然或人造物质时改变神经系统正常活动产生的毒性效应形式。临床上包括为认知和行为问题、记忆智力的丧失等急性或慢性表现。分子生物学上表现为神经细胞的炎性浸润、线粒体功能障碍、诱导细胞凋亡坏死等神经系统功能损伤样改变。SiNPs可经胃肠道、肺-血液、鼻腔和注射等途径进入CNS[2⇓⇓⇓⇓-7]。研究发现SiNPs在大脑中分布主要集中在海马、额叶、颞叶等与NRDs相关的关键脑区[8] ，并且在体内外均能对神经细胞造成损伤，包括但不限于对神经细胞结构功能的破坏、干扰免疫系统和线粒体功能等，病理状态下大脑环境中有害代谢物质的积累与清除障碍，进一步加重损伤。

1.1 SiNPs与神经炎症

NRDs病理条件下活化的小胶质细胞常与神经元的存活率存在一定的关联[9]。小胶质细胞是CNS中具有高度可塑性的常驻先天免疫细胞之一，具有识别、吞噬和清理错误折叠蛋白质和死亡细胞等有害物质的功能，通过与神经细胞之间交互动态监测大脑微环境稳态[10-11]。根据高表达的基因谱将这类小胶质细胞定义为疾病相关的小胶质细胞（disease-associated microglias, DAMs）[12]。Gerrits等[13]研究中也发现两种小胶质细胞与神经病理学标志物组织淀粉样蛋白-β（β-Amyloid, Aβ）斑块和组织过度磷酸化 Tau （p-Tau）密切相关，将这两种细胞分别定义为AD1和AD2小胶质细胞。Aβ和p-Tau是AD主要的病理标志物，DAMs 激活依赖于髓样细胞 2（TREM2）表达的触发受体，特定位点的变异可减少AD易感人群中DAMs活化和斑块沉积关联[14]。有证据直接表明打破激活的小胶质细胞和浸润T细胞之间的免疫中枢可有效防止神经变性病变并减缓认知能力的下降[15]。研究发现，SiNPs可诱导神经炎症，具有导致神经系统损伤的潜在风险。啮齿类动物吸入银硅酸盐纳米颗粒（Ag-SiNPs）可引起嗅球发生短暂但有差异性的小胶质细胞激活，提示其可经嗅球易位到CNS诱导轻度促炎反应[16]。体外实验中，大鼠原代小胶质细胞对不同浓度SiNPs的吞噬作用差异性地上调了细胞内活性氧（reactive oxygen species, ROS）和活性氮（reactive nitrogen species, RNS）水平，并检测到环氧化酶-2（cycooxygenase-2, COX-2）基因表达的增加[17]，通过刺激ROS生成激活下游内质网应激通路诱导神经细胞凋亡，出现细胞密度降低、皱缩等形态学改变[18]。均匀分散于小胶质细胞内的SiNPs，以浓度依赖的形式改变细胞超微结构，使自噬溶酶体增多，内质网呈肿胀，诱导NOD样受体热蛋白结构域相关蛋白3 （NOD-like receptor thermal protein domain associated protein 3,NLRP3）炎性小体的激活[19]，破坏细胞抗氧化能力，释放大量炎性因子如白介素-1β（interleukin-1β，IL-1β)、肿瘤坏死因子（tumor necrosis factor, TNF-α），提示SiNPs可能与神经炎症、小胶质细胞清除功能受损和认知功能障碍相关[20-21]。
以上发现在动物体内研究中也得到了证实，长期吸入SiNPs的小鼠出现全身系统性的炎性相关因子升高和组织纤维化[22]。对MNPs@SiNPs诱导BV2细胞和原代大鼠小胶质细胞转录组网络中基因表达水平定量分析，发现与炎性反应相关的趋化因子呈剂量依赖性上调[23]。另有研究发现介孔二氧化硅纳米颗粒（mesoporous silica nanoparticles，MSNPs）优先聚集于Iba-1阳性的小胶质细胞中，刺激小胶质细胞活化并分泌的具神经兴奋毒性的高浓度D-丝氨酸[23]。Boukholda等[24] 报道了非肠道吸收的SiNPs诱导大脑海马炎性相关因子（TNF-α、IL-1β和COX-2等）mRNA水平显著升高，海马CA3区锥体细胞层厚度降低，呈核固缩、空泡化等改变。SiNPs所致的神经行为改变和脑损伤可能与来源于肠道系统的特殊物质Vipr1和Sstr2对肠-脑轴的破坏，SiNPs处理组脑组织出现神经元减少，细胞萎缩、破裂及核碎裂等病理改变[3]。Ran You等[25]研究显示，与对照组相比，SiNPs处理组小鼠海马CA1、CA3和DG区小胶质细胞基础数量与Iba-1阳性数量呈相同增长趋势，诱导海马组织COX-2蛋白表达水平升高。与Arshiya Parveen等[26]研究结果相似，该研究首次记录了SiNPs对大鼠大脑中核因子κB（nuclear factor κappa-B, NF-κB）、IL-1β和单核细胞趋化蛋白-1（MCP-1）mRNA和蛋白水平表达的刺激作用。最新研究显示，AD早期病理模型APPNL-G-F小鼠情景记忆衰退的同时伴有mPFC-海马CA1背侧神经元异常活跃[27]，该区域神经元的异常活跃也被认为是轻度认知功能障碍的潜在神经机制[28]。基于上述发现，SiNPs在体内外均可能诱导关键脑区神经元数量减少，小胶质细胞的过度激活并调控细胞炎性因子水平的表达，与NRDs病程密切相关。未来研究将进一步探讨SiNPs对小胶质细胞活化和细胞炎性因子水平的具体影响机制，为相关的NRDs的防治提供思路与方法。

1.2 SiNPs与线粒体功能障碍

中枢神经系统发育过程中线粒体是重要调节器[29]，神经元是高度特化的细胞，需线粒体提供大量能量来支持其生长和分化。线粒体还参与维持离子平衡、细胞信号转导、调控细胞周期以及触发细胞凋亡等过程，这些作用共同维系CNS的正常功能。AD患者大脑中存在包括线粒体自噬功能障碍、线粒体动力学受损、线粒体DNA损伤、突触功能障碍等线粒体功能异常（mitochondrial dysfunction, MD）[30]。在线粒体自噬流中，Aβ、p-Tau分别与线粒体分裂蛋白1（Drp1）的异常相互作用诱导AD神经元线粒体过度碎片化，Parkin和PTEN基因诱导激酶1（PINK1）水平减少，最终导致线粒体和神经元的功能受损甚至死亡[30]。
SiNPs可与包括线粒体膜在内的细胞膜相互作用，破坏线粒体膜的完整性和通透性，导致内容物（如细胞色素C）渗漏，促进酸性自噬液泡和自噬体的形成，通过氧化应激介导AMPK/mTOR/P70S6K信号通路调控海马神经元的细胞自噬相关蛋白Beclin-1、LC3BⅡ/Ⅰ和ATG5表达水平[31]，并可诱导多巴胺能神经元变性[32]。另外，MSNPs被报道以粒径大小和时间依赖的方式激活神经元细胞自噬，尤其是线粒体自噬，采用多电极阵列技术发现一定浓度的纳米颗粒可通过增加兴奋性来干扰神经网络活动[33]，并且SiNPs暴露对线粒体功能的影响取决于神经元分化前和分化期间的暴露时间，分化前随暴露时间会显著降低细胞呼吸速率和细胞外酸化速率，分化过程中的暴露可导致线粒体功能障碍，延缓甚至抑制其分化[34]。这些研究结果表明，SiNPs能通过参与调控自噬过程导致细胞无法有效清除受损组分和有害物质，打破细胞稳态，影响细胞周期，诱导细胞凋亡。中枢神经系统疾病中SiNPs作为载体的给药方式广泛应用，还需关注在CNS中SiNPs长期暴露的潜在风险，为纳米材料的生物安全性评估提供更多参考依据。

1.3 SiNPs与Aβ和p-Tau

越来越多的研究表明，SiNPs对NRDs的发生和病程进展具有一定的影响。Aβ聚集形成的斑块和神经元p-Tau形成的神经纤维缠结是AD的主要病理表现。SiNPs可通过干扰Aβ生成和清除、Tau蛋白的磷酸化过程，进而诱导神经细胞发生AD样病理变化。SiNP能显著降低SK-N-SH和N2A细胞系的细胞活力，并导致Aβ1-42沉积和p-Tau水平升高[35]，使小胶质细胞发生细胞肿胀、细胞膜囊泡样改变以及GSDMD介导的细胞焦亡[36]。Tae Hwan Shin等[37]研究结果显示SiNPs与Aβ的积累相关。与对照组相比，经MNPs@SiO2处理的BV2细胞Aβ1-42积累显著增加，蛋白水解作用呈剂量依赖方式减少，并且溶酶体的肿胀与上调的自噬相关蛋白水平相关。利用溶酶体荧光探针在海马神经元中定位到SiNPs在溶酶体内的蓄积[38]，内溶酶体也是β淀粉样前体蛋白（amyloid precursor protein, APP）内化后APP淀粉样变化过程的主要位点，快速和持续性的内溶酶体脱酸可增加内和钙从内溶酶体中的释放，进一步研究中发现在确定无毒浓度（0.01μg/ml或0.1μg/ml）下短时间的SiNPs暴露仍可在原代海马神经元培养基中检测到具有差异性增加的Aβ1-42积累。但SiNPs对Aβ生成和清除的影响及具体机制在体内研究未见报道。值得关注的是，搭载双歧杆菌的介孔SiNPs经鼻腔吸入后缓解了APP/PS1小鼠的肠道炎症，提高其嗅觉灵敏性，而且降低了大脑Aβ负荷[39]。经修饰发挥保护神经细胞免受金属介导的Aβ毒性作用[40-41]，甚至抑制Aβ的聚集[42]。但研究中SiNPs仅是作为载体，并不能确认其是否存在治疗作用。二氧化硅纳米颗粒作为药物载体在其他药物中的应用也需要进一步的研究。研究显示SiNPs对SH-SY5Y的细胞完整性和无定形Tau聚集物的形成产生不利影响[43]。动物长期暴露实验中， SiNPs鼻腔暴露可影响年轻小鼠的认知功能和情绪，上调p-Tau S396位点磷酸化水平，诱导细胞炎性因子释放，丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）通路的激活或可能参与其中[25]。
此外，对CNS的影响并非仅限于成年个体，新生小鼠短期物化吸入SiNPs可诱导海马DG区小胶质细胞的过度激活，抑制神经组织的生物发生，成年后仍可观察到社交互动能力缺陷和轻微的焦虑样行为改变[44]。不同分化时期的SiNPs暴露能降低神经细胞诱导分化的多巴胺能细胞和胆碱能细胞数量[45]。SiNPs亚急性暴露能显著下调大鼠海马组织乙酰胆碱酯酶（AChE）及相关基因ChAT、VAChT、m1AChR和mAChR的mRNA水平，与对照组相比，表现出更显著的焦虑样行为和空间学习记忆障碍[24]。研究显示，煤工尘肺患者群体中存在一定的轻度认知功能障碍比例[46]。矽肺患者血清中较低的脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）水平（≤10 mg/L）与认知功能障碍的发生率具有较高的相关性[47]，提示长期暴露于相关环境中可能存在较高的认知功能障碍发生风险，需要进一步研究SiNPs的神经毒性机制，以便为预防和治疗由SiNPs引起的认知功能障碍相关疾病提供更多依据。

2 SiNPs在神经系统相关疾病治疗中的发展前景

尽管SiNPs潜在的神经毒性风险不可忽视，但研究人员对其在神经系统相关疾病中的应用前景充满期待。SiNPs作为DDS中广泛应用的载体之一，其高比表面积和可调控的表面特性为其在神经系统疾病治疗中的应用提供了广阔的空间，未来SiNPs有望进一步优化其结构设计和制备工艺，以提高药物的靶向性和生物利用度。此外，随着纳米技术和影像技术的不断交融发展，SiNPs在神经系统影像诊断和治疗监测方向的应用也得到进一步拓展。通过引用荧光标记和核磁共振对比剂等技术，SiNPs可实现对神经系统病变更加精准和敏感的检测，为个体化治疗提供更多的可能性，此外，SiNPs还可作为组织工程支架的组成部分，促进神经再生和组织修复[48]，为神经系统损伤和治疗提供新的思路和方法。因此，尽管还存在挑战，但SiNPs在神经系统相关疾病治疗中的发展前景仍然十分广阔。

3 小结

综上所述，SiNPs作为诱导NRDs高风险因素之一，近年的临床前研究显示出SiNPs潜在的神经毒性，可能与其诱导神经炎症、线粒体功能障碍和神经变性样改变相关，但其具体机制尚需进一步探讨，尤其是对线粒体功能的影响与Aβ的生成和清理方面需在动物模型中进行探索。与神经炎症、线粒体功能障碍和神经变性样改变之间的具体关系仍不明确，这限制了我们对其潜在风险和影响的全面理解。对SiNPs在神经系统中相互作用机制的研究有助于指导研究者对载体的选择、药物释放动力学调控等方面的探索。有助于临床更好地监测和预防相关疾病的发生和发展，基于研究结果，制定相应的预防措施，减少患者SiNPs暴露风险。因此，未来研究需深入探讨SiNPs与这些病理过程之间的联系，以便更准确地评估其对神经系统功能的影响，为相关疾病的药物开发和筛选提供可靠的依据。

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