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Volume 41 Issue 3
Mar.  2023
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DAI Yu, WANG Hongbo, BIAN Kangqing, GUO Lingyi, YU Yuan. Progress in preparation and application of biomimetic nano carriers for cell membrane[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(3): 135-138, 145. doi: 10.12206/j.issn.2097-2024.202202058
Citation: DAI Yu, WANG Hongbo, BIAN Kangqing, GUO Lingyi, YU Yuan. Progress in preparation and application of biomimetic nano carriers for cell membrane[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(3): 135-138, 145. doi: 10.12206/j.issn.2097-2024.202202058

Progress in preparation and application of biomimetic nano carriers for cell membrane

doi: 10.12206/j.issn.2097-2024.202202058
  • Received Date: 2022-02-21
  • Rev Recd Date: 2022-04-12
  • Available Online: 2023-07-14
  • Publish Date: 2023-03-25
  • Nanocarriers prepared from organic or inorganic materials are widely used in drug targeting system and diagnosis and treatment of disease. However, there are some problems, such as poor targeting, short circulation time in vivo and improvement in the biocompatibility. Biomimetic nanocarriers has carried out research on the issues, which based on different kinds of cell membrane for the nanocarriers modification, endogenous biofilm improving the biocompatibility of carriers in vivo, more accurate targeting, and even producing immunotherapeutic effect. The principle, method, targeting mechanism and therapeutic effect of biomimetic nano carrier technology of cell membrane have been reviewed in this paper, which provide a new direction for the research of new drug delivery system.
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Progress in preparation and application of biomimetic nano carriers for cell membrane

doi: 10.12206/j.issn.2097-2024.202202058

Abstract: Nanocarriers prepared from organic or inorganic materials are widely used in drug targeting system and diagnosis and treatment of disease. However, there are some problems, such as poor targeting, short circulation time in vivo and improvement in the biocompatibility. Biomimetic nanocarriers has carried out research on the issues, which based on different kinds of cell membrane for the nanocarriers modification, endogenous biofilm improving the biocompatibility of carriers in vivo, more accurate targeting, and even producing immunotherapeutic effect. The principle, method, targeting mechanism and therapeutic effect of biomimetic nano carrier technology of cell membrane have been reviewed in this paper, which provide a new direction for the research of new drug delivery system.

DAI Yu, WANG Hongbo, BIAN Kangqing, GUO Lingyi, YU Yuan. Progress in preparation and application of biomimetic nano carriers for cell membrane[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(3): 135-138, 145. doi: 10.12206/j.issn.2097-2024.202202058
Citation: DAI Yu, WANG Hongbo, BIAN Kangqing, GUO Lingyi, YU Yuan. Progress in preparation and application of biomimetic nano carriers for cell membrane[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(3): 135-138, 145. doi: 10.12206/j.issn.2097-2024.202202058
  • 相对于传统纳米载体而言,由红细胞、血小板、干细胞、巨噬细胞、肿瘤细胞以及细菌等构成的新型内源性载体具有生物相容性好、靶向性高的显著优势[1]。但是,该类细胞载体由于自身理化性质导致其无法在特定组织内渗透和摄取。近年来,随着纳米技术与生物技术的交叉融合,研究者从仿生角度出发,通过物理挤出、共孵育和微流体等技术工艺将各类型天然细胞膜与纳米载体内核相结合,制备出体内循环时间长、生物相容性好、胞内细胞器靶向性能高的新型仿生纳米药物载体[2]。本文综述了细胞膜修饰技术的基本原理及几种最为常用的细胞膜修饰纳米载体的特点及应用。

    • 细胞膜是由磷脂、糖蛋白、糖脂和蛋白质构成的富有弹性的半透性膜,其中,磷脂双分子层是构成细胞膜的基本结构,其在广泛的生物功能中发挥着重要作用。细胞膜的提取包括膜溶解和膜纯化[3],具体过程由所提取的细胞类型决定。对于无核细胞(如哺乳动物成熟红细胞和血小板),可通过低渗处理或者反复冻融破坏其细胞膜,差速离心去除可溶性蛋白质,然后通过挤压形成由细胞膜构成的囊泡[4]。对于白细胞、癌细胞和干细胞等真核细胞,膜提取过程则相对复杂。首先,需要从组织或血液中分离目标细胞,之后先进行细胞培养[5],再将培养好的细胞通过低渗裂解、机械膜破坏和蔗糖梯度离心相结合的方法去除细胞核和细胞质,从而分离出细胞膜[6]。分离出的细胞膜用等离子缓冲剂彻底清洗后,通过多孔聚碳酸酯膜挤压形成纳米囊泡[7]

    • 内核纳米材料在细胞膜仿生纳米载体技术中至关重要[8]。近年来,各种类型的纳米材料(如聚合物纳米粒、脂质体、二氧化硅、介孔二氧化硅、金粒子、氧化铁、金属-有机骨架、纳米凝胶和黑磷等)已成为细胞膜仿生技术的核心载体。由脂质和聚合物为材料制备的纳米载体因其良好的生物相容性和高载药量,广泛用于制备纳米粒子[9]。无机材料具有成本低、易于进行化学结构修饰及特定光电磁性质的显著优势,可以更好地控制无机颗粒的表面组成、形状和尺寸,并且可以用适当的膜囊进行伪装[8]。最新研究发现,纳米凝胶由于其大孔结构和高负载能力而成为理想的内核载体材料[10];同时,Chen等[11]利用黑磷优良的光热性能、负电位及生物降解性将其与红细胞膜融合制备成为光热治疗剂,结果表明该方法能够有效抑制乳腺癌细胞的生长。

    • 目前,常用的生物细胞膜与纳米载体融合方法有薄膜挤压法、超声融合法和电穿孔法。薄膜挤压法借助挤压器通过纳米级聚碳酸酯多孔膜反复挤压,利用机械力使纳米材料与细胞膜相融合[12],该方法工艺简便,但难以大规模制备。超声融合法是将纳米粒子与细胞膜共孵育后利用超声促进细胞膜的包覆,但是该方法生成的载体颗粒均一性较差[13]。微流控电穿孔法将载体各组分在Y形通道中完全混合,通过电穿孔制备出性质稳定、包覆率高的纳米载体[14]

    • 细胞膜纳米粒子的评估包括物理、化学和生物特性3个方面,以确定细胞膜是否成功地包覆在纳米粒子表面。细胞膜包覆的效率取决于纳米粒子的大小、表面电荷和蛋白质组成。细胞膜改变了纳米粒子大小和Zeta电位,透射电子显微镜(TEM)可用于确认细胞膜纳米粒子的形态,与未包覆的纳米粒子相比,粒子直径明显增加。Zeta电位表明了细胞膜包覆前后颗粒表面的电位特征。Fan等[15]以红细胞膜包覆后,颗粒的Zeta电位增加了10mV。另外,可通过动态光散射(DLS)验证细胞膜纳米粒子的粒径分布[16]。细胞膜的仿生功能主要取决于其生物学特性。因此,验证膜的生物活性是至关重要的,从而确保最佳的纳米粒子包覆效能。蛋白免疫印迹法常被用于鉴别包覆于纳米粒上的细胞膜蛋白,从而验证纳米载体的生物特性,Wang等[17]通过该方法证实了红细胞膜特征蛋白CD47存在于被红细胞膜包覆的纳米粒子表面。

    • 经天然细胞膜包覆后的纳米粒子生物相容性增强,具有特异性识别靶部位、靶组织和靶细胞的特性。近年来,各种类型的天然细胞已被广泛应用于纳米载体制备,如红细胞、血小板、免疫细胞、癌细胞,甚至细菌膜,以大肠杆菌为膜源,组装构建出具有多种功能的生物复合传递系统,发挥其特殊的靶向和治疗作用。

    • 红细胞由于自身生物特性(例如红细胞表面跨膜蛋白CD47),能够在体内不受免疫系统的攻击[18],利用红细胞膜包覆纳米粒子制备成的药物载体具有循环时间长和免疫逃避特性等显著优势[19]。Fang等[20]通过挤压法和超声法将红细胞囊泡与叶酸和核苷靶向适体AS1411相融合,结果显示该方法获得的红细胞膜纳米载体能够显著提高肿瘤靶向性和治疗效果。红细胞膜表面有各种成孔毒素相关特异性受体成分,且具有磷脂双分子层结构,因此有广谱的成孔毒素中和作用且生物相容性好。经红细胞膜包覆的纳米粒子可以吸附多种成孔毒素(如α-溶血素、链状溶血素-O等),并保护红细胞免受溶血[21]。研究显示这些纳米粒子并没有将毒素转移到宿主细胞,确保了生物安全性。同时,将灭活毒素整合到纳米粒子的细胞膜中作为类毒素疫苗,对受到耐甲氧西林金黄色葡萄球菌攻击的小鼠具有明显保护作用,能显著减少相关肺损伤,并抑制脾脏炎症转录因子的激活。通过利用红细胞血液循环时间长和“自我标记”蛋白的特性,这些仿生纳米粒子可以避免免疫细胞对其捕获。

    • 血小板具有广泛的抗原和功能蛋白,并在肿瘤转移中发挥重要作用,其被开发成为细胞膜材料[22],可用于多发性骨髓瘤和血栓治疗、动脉粥样硬化检测、癌症治疗以及控制细菌感染。Wei等[23]用血小板膜包覆纳米粒子以清除体循环中的病理性抗体,这一策略被用来治疗免疫性血小板减少性紫癜,能有效地减少血小板的破坏,并保持正常的止血功能。Ávila等[24]研究发现,用红细胞膜和血小板膜的混合物包覆纳米粒子使其成为优良的解毒剂,赋予纳米粒子许多新的生物学特性,包括结合黏附于血小板的病原体(如金黄色葡萄球菌细菌)以及中和成孔毒素(如志贺毒素和金黄色葡萄球菌)。

    • 各类免疫细胞(例如巨噬细胞、中性粒细胞、树突状细胞、干细胞及T细胞)能够在机体产生免疫反应的第一时间被招募至特定位置发挥免疫功效[25-26],使其成为包覆纳米载体的理想载体膜。Xuan等[27]研究发现,经巨噬细胞膜包覆的二氧化硅纳米粒子在体内的循环时间明显延长,并能够提高阿霉素的传递效率和抗癌效果。同时,Xuan等[28]用巨噬细胞膜包覆近红外成像探针(Cy7)载金纳米粒子,能够增加药物在肿瘤组织的积聚,在近红外激光照射下,由巨噬细胞膜包覆的金纳米粒子产生的局部热量可高效抑制肿瘤生长,并选择性地消融热辐射区域内的癌细胞。Zhang等[29]用巨噬细胞膜包覆对酸碱度敏感的聚合物纳米粒子,用于肿瘤靶向化疗,具有响应肿瘤微环境刺激的控释特性。其将紫杉醇传递至靶向位置,发现该载体能够使药物在肿瘤低pH值环境中充分释放。中性粒细胞在免疫反应中扮演重要角色[30]。Gao等[31]研究发现,基于中性粒细胞膜纳米囊泡药物递送系统可选择性地靶向于炎症血管部位释药,以逆转急性肺部炎症。Zhang等[32]将人的外周血中性粒细胞膜包覆在聚乳酸-羟基乙酸(PLGA)聚合物芯上,构建炎症治疗平台,从而抑制滑膜炎症并减轻炎症性关节炎受试者的关节损伤。此外,Wei等[33]将人T淋巴瘤细胞(SUP-T1)的细胞膜包覆在聚乳酸-羟基乙酸共聚物(PLGA)上,T细胞膜包覆纳米粒子后可选择性地与HIV的糖蛋白gp120结合,并抑制gp120诱导的对CD4+T细胞的杀伤。当加入到HIV病毒中时,T细胞膜包覆纳米粒子以剂量依赖性的方式有效地中和外周血单个核细胞和人类单核细胞源性巨噬细胞的病毒感染。通过利用天然T细胞功能,T细胞膜包覆纳米粒子作为一种新的抗HIV感染治疗剂显示出巨大的潜力。干细胞作为一种“万能细胞”,在不同发育阶段都具有靶向肿瘤细胞的特性[34]。Cao等[35]研究了一种新型抗癌药物载体,即包封载药空心二氧化硅纳米颗粒的间充质干细胞(MSCs),由于MSCs天然的高肿瘤亲和力,用于携带光敏剂药物并将其输送至乳腺肿瘤,并通过光动力学疗法抑制肿瘤生长。这种新策略解决了光动力疗法中光敏剂药物在肿瘤中积聚的问题,并成功用于肿瘤靶向治疗。

    • 癌细胞具有无限复制潜能、免疫逃逸、循环时间长和同源结合能力等独特功能[36],从而使癌细胞膜成为设计抗癌纳米递药系统的包覆材料[37]。Chen等[38]构建了一个核心−外壳的纳米结构ICNP,由吲哚青绿(ICG)和人乳腺癌细胞膜(MCF-7)外壳组成。ICNP表现出对癌细胞的特异性同源靶向性,具有良好的单分散性、较好的光热响应和优异的荧光/光声成像特性。得益于来自癌细胞膜的同源结合黏附分子的功能化,ICNP显著促进细胞内吞和体内同源靶向肿瘤积聚; 在近红外激光照射下,ICNP表现出高效的光热疗法来根除异种移植肿瘤,具有癌细胞膜同源性的ICNP可以作为肿瘤靶向成像和光疗的仿生纳米平台。Yang等[6]将甘露糖修饰的黑色素瘤细胞膜包覆在一种负载受体7激动剂(咪喹莫特)的PLGA纳米粒子上组成的抗癌疫苗,可使其被树突状细胞更好地摄取,从而触发机体对癌细胞的特异性免疫反应,延缓了肿瘤的发展恶化。Sun等[39]用4T1乳腺癌细胞膜包覆负载紫杉醇的聚合物纳米粒子,结果发现该载体可以选择性地积聚在原发性肿瘤和转移性结节中,血液清除速度较慢,并且显著抑制转移性肿瘤和原发性肿瘤的生长。其研究还可能通过使用癌症患者的肿瘤细胞膜作为药物载体,为转移癌的个性化治疗开辟一条新途径。以上研究可以发现,将不同的肿瘤细胞膜开发为膜包覆材料,利用其特异性的靶向能力,在肿瘤治疗方面具有广阔的应用前景。

    • 与基于细胞的仿生系统一样,细菌的蛋白质外壳与功能性纳米颗粒结合,广泛应用于药物输送、肿瘤成像和治疗[40]。鉴于其高水平的免疫原性蛋白和佐剂特点,细菌细胞膜在病原体相关分子靶点介导和适应性免疫系统激活的环境中可用于纳米粒子修饰[41]。Gao等[42]用大肠杆菌衍生膜包覆30nm的金纳米粒子并将其注射于小鼠皮下,结果发现这些粒子能被运送到近端引流淋巴结,并能激活树突状细胞。同时,接种了大肠杆菌膜纳米粒子的小鼠比仅接种了外膜囊泡的小鼠表现出更高的抗体亲和力和IFN-γ及IL-17水平,该结果证实被大肠杆菌包覆的纳米粒子载体能够特异性激活T细胞免疫反应。Zhang等[43]将光敏剂原卟啉IX和抗菌肽2结合起来,制备出对细菌光动力疗法失活的PPK颗粒,这些颗粒能够通过静电相互作用和膜渗透结合在细菌细胞上,进而破坏细菌细胞膜组织起到杀菌作用。

      细菌细胞膜包覆纳米粒子不仅能简化细菌载药系统,而且能构建纳米级别的靶向载药系统。但是,该方法也对生物安全性提出一些需研究问题,如细菌细胞膜的抗原特性,是否会引起感染相关问题仍需进一步的研究。

    • 细胞膜仿生纳米粒子将包覆材料和内源性生物材料进行融合,进一步激发从生物学角度设计新型给药系统的创新发展。细胞膜包覆的纳米粒子将在体内药物递送、生物成像和疾病治疗,特别是癌症的诊断和治疗方面显示出许多优势。然而,使用单一类型或常规类型的细胞膜作为包覆材料可能会限制其功能多样性,混合类型的细胞膜与纳米载体共同构建高选择性的靶向药物输送系统具有广泛的研究价值。结合全面的生物特性和功能,整合纳米材料将增强治疗性纳米粒子的体内性能。例如,可以考虑将由抗体、脱氧核糖核酸/核糖核酸、肽、蛋白质和酶组成的简易配体修饰于细胞膜,从而增强精准靶向性能,甚至是协同的治疗作用。尽管细胞膜仿生技术尚未完全实现临床应用,但其明显的优势和丰富的细胞膜来源为其工业化生产和在个体化精准医学中的实施提供了坚实的基础。

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