药学学报

Source	Biomarker	Characteristic advantage	Limitation	Disease	Ref.
RBCs	CD47	Long cycle times, high availability, high biocompatibility, simple membrane surface modification process	Lack of targeting	NSCLC, protect the pulmonary vascular barrier	37-39
Platelets	P-selectin, CD47	Inflammation targeting, immune escapes	Easy aggregation in vitro	Lung cancer, lung metastasis of breast cancer, pneumonia, allergic asthma	40-43
Cancer cells	T antigen-galectin-3, CD47	Homologous localization, strong targeting ability	Potential security issues that may have side effects	NSCLC, lung metastasis of breast cancer, pneumonia	46-48
MSCs	CXCR4, CD74	Inherently tumor homing and inflammatory migration	Inconvenient to extract in large quantities	Pneumonia, NSCLC, metastatic carcinoma of lung, pulmonary fibrosis	53, 58-60
Immune cells	α4 Integrins, CD45, CD47	Immune evasion, targeting of metastatic tumors	Complex workflow for extracting and purifying membranes, uncertain immune responses	Metastatic carcinoma of lung, pneumonia, NSCLC	68, 69, 71, 72, 74
Bacteria	Virulence factors	Immune activation, easy in vitro expansion, relatively easy genetic engineering	Dose-limiting toxicity	Pneumonia	79

Source

Biomarker

Characteristic advantage

Limitation

Disease

Ref.

RBCs

CD47

Long cycle times, high availability, high biocompatibility, simple membrane surface modification process

Lack of targeting

NSCLC, protect the pulmonary vascular barrier

37-39

Platelets

P-selectin, CD47

Inflammation targeting, immune escapes

Easy aggregation in vitro

Lung cancer, lung metastasis of breast cancer, pneumonia, allergic asthma

40-43

Cancer cells

T antigen-galectin-3, CD47

Homologous localization, strong targeting ability

Potential security issues that may have side effects

NSCLC, lung metastasis of breast cancer, pneumonia

46-48

MSCs

CXCR4, CD74

Inherently tumor homing and inflammatory migration

Inconvenient to extract in large quantities

Pneumonia, NSCLC, metastatic carcinoma of lung, pulmonary fibrosis

53, 58-60

Immune cells

α4 Integrins, CD45, CD47

Immune evasion, targeting of metastatic tumors

Complex workflow for extracting and purifying membranes, uncertain immune responses

Metastatic carcinoma of lung, pneumonia, NSCLC

68, 69, 71, 72, 74

Bacteria

Virulence factors

Immune activation, easy in vitro expansion, relatively easy genetic engineering

Dose-limiting toxicity

Pneumonia

Source	Biomarker	Characteristic advantage	Limitation	Disease	Ref.
RBCs	CD47	Long cycle times, high availability, high biocompatibility, simple membrane surface modification process	Lack of targeting	NSCLC, protect the pulmonary vascular barrier	37-39
Platelets	P-selectin, CD47	Inflammation targeting, immune escapes	Easy aggregation in vitro	Lung cancer, lung metastasis of breast cancer, pneumonia, allergic asthma	40-43
Cancer cells	T antigen-galectin-3, CD47	Homologous localization, strong targeting ability	Potential security issues that may have side effects	NSCLC, lung metastasis of breast cancer, pneumonia	46-48
MSCs	CXCR4, CD74	Inherently tumor homing and inflammatory migration	Inconvenient to extract in large quantities	Pneumonia, NSCLC, metastatic carcinoma of lung, pulmonary fibrosis	53, 58-60
Immune cells	α4 Integrins, CD45, CD47	Immune evasion, targeting of metastatic tumors	Complex workflow for extracting and purifying membranes, uncertain immune responses	Metastatic carcinoma of lung, pneumonia, NSCLC	68, 69, 71, 72, 74
Bacteria	Virulence factors	Immune activation, easy in vitro expansion, relatively easy genetic engineering	Dose-limiting toxicity	Pneumonia	79

Source

Biomarker

Characteristic advantage

Limitation

Disease

Ref.

RBCs

CD47

Long cycle times, high availability, high biocompatibility, simple membrane surface modification process

Lack of targeting

NSCLC, protect the pulmonary vascular barrier

37-39

Platelets

P-selectin, CD47

Inflammation targeting, immune escapes

Easy aggregation in vitro

Lung cancer, lung metastasis of breast cancer, pneumonia, allergic asthma

40-43

Cancer cells

T antigen-galectin-3, CD47

Homologous localization, strong targeting ability

Potential security issues that may have side effects

NSCLC, lung metastasis of breast cancer, pneumonia

46-48

MSCs

CXCR4, CD74

Inherently tumor homing and inflammatory migration

Inconvenient to extract in large quantities

Pneumonia, NSCLC, metastatic carcinoma of lung, pulmonary fibrosis

53, 58-60

Immune cells

α4 Integrins, CD45, CD47

Immune evasion, targeting of metastatic tumors

Complex workflow for extracting and purifying membranes, uncertain immune responses

Metastatic carcinoma of lung, pneumonia, NSCLC

68, 69, 71, 72, 74

Bacteria

Virulence factors

Immune activation, easy in vitro expansion, relatively easy genetic engineering

Dose-limiting toxicity

Pneumonia

膜仿生纳米载体在肺部疾病靶向治疗中应用研究进展

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白文静 ¹ , 郭蓉 ² , 熊淋 ¹ , 朱冷静 ¹ , 李嘉欣 ¹ , 王雅施 ¹ , 李曼 ¹ , 何勤 ¹^,^*

药学学报 | 综述 2024,59(10): 2730-2740

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药学学报 | 综述 2024, 59(10): 2730-2740

膜仿生纳米载体在肺部疾病靶向治疗中应用研究进展

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白文静¹, 郭蓉², 熊淋¹, 朱冷静¹, 李嘉欣¹, 王雅施¹, 李曼¹, 何勤¹^,^*

作者信息

1.四川大学华西药学院, 靶向药物及释药系统教育部重点实验室, 四川成都 610041

2.四川大学华西基础医学与法医学院, 四川成都 610041

通讯作者:

^*何勤, Tel: 86-28-85502532, E-mail: qinhe@scu.edu.cn

Research progress on the application of membrane biomimetic nanocarriers in targeted therapy of lung diseases

Wen-jing BAI¹, Rong GUO², Lin XIONG¹, Leng-jing ZHU¹, Jia-xin LI¹, Ya-shi WANG¹, Man LI¹, Qin HE¹^,^*

Affiliations

1. Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China

2. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China

出版时间: 2024-10-12 doi: 10.16438/j.0513-4870.2023-1205

文章导航

摘要

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肺部疾病是人类健康的主要威胁之一, 目前针对肺部疾病的临床治疗药物普遍存在肺部递送效率低、清除速率快及毒副作用明显等问题。近年来, 膜仿生纳米载体受到越来越多的关注, 因其具有靶向性高、循环时间长、生物相容性好和免疫逃逸能力强等优势, 已成为肺部疾病靶向治疗的一大研究热点。本文综述了膜仿生纳米粒的主要制备方法、不同细胞来源的膜仿生纳米载体的特点及其在肺部疾病靶向治疗中的应用; 此外, 结合不同膜的性质特点分别讨论其缺点, 并讨论当前的技术局限性及未来的展望, 为膜仿生纳米载体的设计及其在肺部疾病治疗中的潜在应用提供参考。

关键词

肺部疾病 / 肺靶向 / 细胞膜 / 膜仿生纳米载体 / 药物递送系统

Abstract

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Pulmonary disease is one of the major threats to human health. However, the current clinical treatment drugs for lung diseases generally have problems such as low lung delivery efficiency, fast clearance rate and obvious toxic side effects. Recently, membrane biomimetic nanocarriers have attracted more and more attention. Due to their advantages of high targeting, long cycle time, good biocompatibility and strong immune escape ability, membrane biomimetic nanocarriers have become a major research hotspot in targeted therapy of lung diseases. In this review, we discuss the main preparation methods of membrane biomimetic nanoparticles, the characteristics of membrane biomimetic nanocarriers from different cell sources and their application in the targeted therapy of lung diseases. At the same time, according to the characteristics of different membranes, the shortcomings, current technical limitations and future prospects are discussed. This review is expected to provide references for the design of membrane biomimetic nanocarriers and their potential applications in the treatment of lung diseases.

Key words

pulmonary disease / lung targeted / membrane / biomimetic nanoparticle / drug delivery system

引用本文

白文静, 郭蓉, 熊淋, 朱冷静, 李嘉欣, 王雅施, 李曼, 何勤. 膜仿生纳米载体在肺部疾病靶向治疗中应用研究进展. 药学学报, 2024 , 59 (10) : 2730 -2740 . DOI: 10.16438/j.0513-4870.2023-1205

Wen-jing BAI, Rong GUO, Lin XIONG, Leng-jing ZHU, Jia-xin LI, Ya-shi WANG, Man LI, Qin HE. Research progress on the application of membrane biomimetic nanocarriers in targeted therapy of lung diseases[J]. Acta Pharmaceutica Sinica, 2024 , 59 (10) : 2730 -2740 . DOI: 10.16438/j.0513-4870.2023-1205

正文

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肺部疾病是重大的全球公共卫生问题^[1], 对人类健康造成巨大威胁^[2], 主要包括肺部感染^[3]、急性肺损伤^[4]、肺癌^[5]、哮喘^[6]、囊性纤维化^[7]等。全世界六大死亡原因中有三个是肺部疾病, 每年导致760万人死亡^[8]。目前, 针对肺部疾病的治疗, 临床治疗药物普遍存在肺部递送效率低^[9]、清除速率快^[10]及毒副作用明显^[11]等问题。

为解决传统治疗措施中存在的问题, 研究者致力于开发肺靶向递药系统, 以实现药物在病理性肺组织中的高效递送^{[12, 13]}。经肺部吸入^[14]或静脉注射的纳米颗粒是目前最常见的肺靶向递药系统^{[15, 16]}, 已在多种肺部疾病模型中取得了良好的治疗效果。然而, 这些靶向递药系统仍然存在一定的局限性。例如, 经肺部吸入的纳米颗粒在气道和肺泡中很容易被黏液层、支气管肺泡液和吞噬细胞吞噬^[17], 而经静脉注射的纳米颗粒容易被网状内皮系统吞噬, 并经肾脏、肠和肝脏代谢清除^[18-20], 导致纳米颗粒在肺组织的分布减少。另外, 分散的纳米颗粒倾向于吸附各种蛋白质, 形成蛋白冠, 使纳米颗粒的靶向能力降低^[21]。因此, 如何克服生理屏障, 提高纳米颗粒在肺部的靶向递送效率已成为亟待解决的难题。

近年来, 基于活细胞的肺靶向递药系统受到了越来越多的关注。与普通的纳米颗粒相比, 活细胞药物载体具有天然的靶向性, 同时还具有免疫原性低、安全性好的优势。常用于药物递送的细胞主要包括红细胞(red blood cell, RBC)、间充质干细胞(mesenchymal stem cell, MSC)、血小板(platelet, PLT)、巨噬细胞等。具体而言, 药物可以封装在细胞内^[22], 也可以吸附在细胞表面^[23]。

然而, 活细胞作为载体的方法面临诸多问题。首先, 活细胞载药策略尚未标准化, 并且药物释放不可控, 如抗癌药物细胞毒性和药物快速外排导致的损失; 其次, 有研究表明, 静脉注射后, 因为细胞大小滞留在肺部的间充质干细胞会诱发肺栓塞^[24], 如间充质干细胞可以通过抑制抗原特异性T细胞增殖和促进调节性T细胞的产生来调节免疫反应的强度, 由此抑制免疫反应和促进肿瘤生长和转移的能力, 其中微环境可能会影响间充质干细胞的行为^[25]; 此外, 间充质干细胞具有分化潜力, 在应用中不能排除分化为不相关细胞的风险^[26]。

在此基础上, 研究者进一步开发了细胞来源的膜仿生纳米载体。通过将生物膜涂覆在纳米颗粒表面, 可以伪装纳米颗粒, 赋予它们天然细胞的固有特性^[27]。研究表明, 膜片段即使在与细胞源分离后仍保留其生物学内容和膜蛋白谱, 因此, 膜仿生纳米载体在保留了核纳米颗粒各种基本性质的同时, 还具有良好的靶向性和生物相容性^[28]; 此外, 细胞膜的包被还可以帮助纳米颗粒在递送药物的过程中保持完整的结构和功能^{[29, 30]}。综上所述, 细胞来源的膜仿生纳米载体有望为肺部疾病提供潜在的靶向治疗策略。

1 膜仿生纳米载体的制备方法

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膜仿生纳米粒的主要制备方法包括膜挤出、超声处理和微流体电穿孔。

膜挤出是最常用的方法, 是一种通过施加机械压力将纳米颗粒封装在细胞膜中以促进纳米颗粒渗透到细胞膜的磷脂双层的方法^[31]。根据纳米颗粒尺寸, 通过使用具有不同孔径的多孔膜过滤器将提取的膜与其他纳米结构共挤出, 以产生具有壳核结构的膜仿生纳米载体^[32]。然而, 机械挤出可能需要较大的压力来挤压硬颗粒, 并且对于实现大规模制备仍然具有挑战性。

超声处理是制备膜仿生纳米颗粒的另一种主要方法, 其中细胞膜和纳米颗粒在超声波能量提供的破坏力下自组装形成核壳纳米结构^[33]。与膜挤出相比, 这种方法具有材料损失更少的优点。值得注意的是, 应仔细考虑和优化超声处理的持续时间、频率和功率, 以尽量减少超声处理可能损坏的膜相关成分, 同时最大限度地提高融合效率。

另一种更有效和更简单的膜包被技术是微流体电穿孔, 是最近开发的一种制备膜仿生纳米颗粒的技术, 显示出作为具有可控、可调和可扩展潜力的制备技术^[34]。在该方法中, 纳米颗粒和细胞膜囊泡在微流控芯片中混合, 然后流过电穿孔区。两个电极之间的电脉冲可以有效地促进纳米颗粒进入细胞膜囊泡。对于此过程, 必须适当设置微流控芯片上的流速, 持续时间和脉冲电压, 以确保纳米结构完全被细胞膜覆盖。由于微流控电穿孔的诸多优点(如高通量、低成本和精细可控性), 它被认为为扩大细胞膜衍生纳米结构的应用提供了强大的工业前景。

2 不同细胞来源的膜仿生纳米载体

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膜仿生纳米载体的性质在很大程度上取决于细胞膜上功能蛋白的种类和数量, 可针对不同靶点选择不同细胞膜^[35]。本部分将介绍目前不同细胞来源的膜具有的功能蛋白及不同细胞来源的膜仿生纳米载体在肺部疾病中的应用研究(图 1)。

2.1 红细胞来源的膜仿生纳米载体

RBC是人体中最丰富的血细胞, 负责为细胞和组织提供氧气并将二氧化碳输送到肺部。由于从血液中分离RBC的便利性和RBC的无核特性, RBC是用于制备膜仿生载体的第一类细胞, 将RBC膜涂覆在粒径约100 nm的聚乳酸-羟基乙酸共聚物(PLGA) 颗粒表面^[36]。旨在用RBC外部伪装纳米颗粒表面以进行长时间循环, 同时保持聚合物核心的适用性。

RBC膜上表达的自我识别蛋白CD47被网状内皮系统识别, 可以欺骗宿主免疫系统并避免蛋白冠的合成, 从而提高生物相容性并延长保留时间, 使RBC膜具有循环时间长的优点, 也因此广泛用于肺部疾病的治疗^[37]。例如, 制备红细胞膜包被的甲磺酸奥巴托克拉(OM) 负载的PLGA纳米颗粒, 显示出改善的肺肿瘤抑制和良好的生物相容性。与裸纳米颗粒相比, 红细胞膜包被的纳米颗粒实现长期体循环, RBCm-OM/PLGA表现出比游离OM注射液更长的相对生物利用度, 几乎是游离OM注射液的4倍, 因此对非小细胞肺癌(NSCLC) 细胞表现出更强的细胞毒性, RBCm-OM/PLGA高度诱导NSCLC细胞中的caspase-3/7活性, 较裸纳米粒约提高2倍^[38]。若要实现靶向效果则需要对RBC膜表面进行修饰。有研究表明, 通过将1, 2-二氨基环己烷-铂(II) (DACHPt) 和吲哚菁绿(ICG) 包封的牛血清白蛋白(BSA) 包埋在靶向肽修饰RBC膜(R-RBC@BPtI) 中, 构建了一种具有肿瘤靶向能力的新型RBC膜仿生联合治疗体系R-RBC@BPtI (图 2), 通过光热和化疗联合实现了显著的肿瘤消融和体内肺转移抑制^[39]。

2.2 血小板来源的膜仿生纳米载体

与RBC相比, PLT膜包被的纳米颗粒具有靶向肿瘤和受损血管黏附的能力, 是由于P-选择素在PLT上过表达, 这使得PLT能够特异性地与肿瘤细胞表面过表达的CD44受体结合^[40]。例如, 作者以内皮特异性启动子Tie2和缺氧反应元件血管紧张素转换酶2 (ACE2) 构建缺氧响应质粒, 并以鱼精蛋白(protamine, PRT) 和硫酸软骨素(chondroitin sulfate, CS) 为核心包装质粒, 然后以PLT膜为壳, 制备仿生纳米颗粒递送系统ACE2-CS-PRT@PM, 靶向受损肺血管内皮^[41]。ACE2-CS-PRT@PM有效地将缺氧响应的ACE2质粒递送到肺血管内皮细胞中, 仅在缺氧环境中促进ACE2的过表达, 治疗缺氧性肺动脉高压(hypoxic pulmonary hypertension, HPH) (图 3)。在HPH大鼠中, ACE2-CS-PRT@PM主要存在于3 h的肺和肝脏中, 12 h时存在于肺、肝和肾脏中, 24 h仅存在于肺中, 而裸纳米粒主要存在于3 h的肝脏和肺中, 12 h时仅存在于肾脏中, 24 h时完全清除, ACE2-CS-PRT@PM在HPH大鼠中表现出更好的肺靶向和较慢的清除速度, 并在很大程度上逆转HPH, 减少肺血管重构, 恢复肺内血管紧张系统平衡。

同时, PLT膜包被的纳米颗粒应用于抑制肿瘤肺部转移。例如, 构建了基于MnOx纳米化的工程纳米血小板(MOAP) 用于肿瘤内局部光热免疫治疗, 可抑制肺转移^[42]。此外, 由于炎症靶向能力, PLT膜涂层有利于治疗肺部炎症。例如, 合成PLGA纳米颗粒以共包封姜黄素(curcumin, Cur) 和白藜芦醇(resveratrol, RV), 并将PLT膜包被到Cur-RV NPs上以形成PM@Cur-RV NPs靶向炎症^[43]。构建PM/Ber纳米颗粒用于将小檗碱(Ber) 输送到炎症肺。PM/Ber在静脉注射后2 h成功靶向肺部炎症病灶, 从而减轻过敏性哮喘。

2.3 肿瘤细胞来源的膜仿生纳米载体

肿瘤细胞的快速体外扩增使得大量分离细胞膜成为可能^[28]。肿瘤细胞膜富含多种功能蛋白, 包括介导同源结合的膜蛋白(整合素αvβ3、E-钙粘蛋白等)^[44]、自我识别和免疫逃逸的生物标志物(CD47等)^[45]和免疫激活相关的肿瘤抗原(肿瘤相关汤姆森-弗里登赖希糖原等)^[46]。因此, 肿瘤细胞膜仿生纳米载体作为药物递送策略被认为是一种有潜力的选择, 因为它们能够逃避免疫监视和靶向肿瘤部位。

利用肿瘤细胞膜包被负载奥希替尼(osimertinib, Osi) 的聚合物纳米颗粒(NP@Osi) 得到的仿生纳米颗粒(CMNP@Osi) 具有用于抗肿瘤治疗的体内双重靶向^[47]。此外, 肿瘤细胞膜伪装的CMNP@Osi表现出延长体内清除时间及由黏附分子和肿瘤特异性结合蛋白介导的同型靶向, 与肿瘤细胞的结合蛋白非常相似。CMNP@Osi还显示出同源肿瘤细胞的有效摄取, 随后将Osi释放到细胞质中, 该细胞质与内膜上的EGFR酪氨酸激酶受体结合, 增强分子靶向并实现有效的肺癌治疗。此外, 有研究表明转移性乳腺癌外泌体由于其独特的表面标志物表达谱而具有天然肺部亲和性, 其包裹装有抗炎药地塞米松的核心纳米颗粒得到的仿生纳米粒被证明具有天然肺部亲和性^[48]。在体内, 这些纳米颗粒在肺组织中表现出增强的积累, 并显著降低肺部炎症模型中的促炎细胞因子负荷(图 4)。该项研究将肿瘤细胞源生物膜材料扩展到非肿瘤的肺部炎症疾病中。

2.4 干细胞来源的膜仿生纳米载体

一些干细胞, 如MSC、胚胎干细胞和神经干细胞, 是具有自我复制能力的分化细胞^[49]。此外, 干细胞具有归巢能力, 通过将靶器官释放的趋化因子、黏附分子和生长因子与干细胞表面表达的相应受体相结合, 使干细胞靶向到受损器官^[50]。特别是, MSC显示出有效的肿瘤归巢和炎症诱导迁移的固有能力^{[51, 52]}, 这与其归巢受体的表达密切相关, 一个典型的例子是C-X-C趋化因子受体4型(CXCR4), 由于对发炎组织释放的基质细胞衍生因子1α (SDF-1α) 的反应, 它被认为在炎症诱导的MSC迁移中起着至关重要的作用^[53]。发炎的组织产生多种细胞因子, 这些产生的细胞因子会进一步扩散到血液循环并形成趋化因子梯度, 这将激活MSC上表达的相应受体, 如CXCR4, 并启动MSC沿细胞因子梯度的迁移。这种性质使MSC具有固有的炎症靶向性和在炎症部位的长期保留^[54]。此外, MSC上也有很多黏附分子表达, 如迟现抗原-4 (VLA-4) 和分化簇44 (CD44)^[55]。这些黏附分子对于MSC在血液中滚动期间附着在发炎的血管内皮细胞上至关重要, 允许MSC随后的内皮迁移以进一步迁移到发炎的肺细胞^[56]。

由于肺血管系统的过滤功能, 大多数静脉内给药的MSCs最初在肺部被拦截, 然后迁移到肺部的受伤区域^{[56, 57]}。该特性赋予MSC优异的肺部靶向能力, 非常适合于肺部疾病靶向治疗。MSC作为成功治疗肺肿瘤^{[58, 59]}和肺纤维化(PF)^[60]的强大肺靶向载体, 在患病细胞特化靶向和患病肺长期保留方面显示出显著优势。有研究利用MSC在糖酵解状态下能量需求较少, 有利于线粒体转移到患病细胞, 并且MSC对病变组织具有显著的归巢能力, 为靶向线粒体转移提供了可能性的优点, 使其成为线粒体供体细胞, 提出了基于氧化铁纳米颗粒(IONP) 的MSC工程, 以提高其细胞间的线粒体转移速率, 治疗PF^[60]。

然而, 由于MSC的给药具有诱发肺微栓塞的潜在风险^[61], 利用MSC膜涂层的仿生纳米颗粒作为替代选择, 以利用炎症归巢的优势, 同时避免直接使用MSC的潜在风险。例如, 将抗病毒药物更昔洛韦(GCV) 和磷酸甲酸酯(PFA) 加载到由聚乳酸-乙醇酸(PLGA) 和1, 2-二油酰基-3-三甲基铵丙烷(DOTAP) 制备的pH响应纳米颗粒中, 并进一步包被源自骨髓间充质干细胞的细胞膜, 形成人工干细胞MPDGP (图 5)。在巨细胞病毒(CMV) 诱导的肺炎模型中, 包被骨髓间充质干细胞膜的仿生纳米粒MPDGP表现出明显的炎症嗜性, 并有效抑制病毒复制和病毒感染相关炎症^[62]。

2.5 免疫细胞来源的膜仿生纳米载体

免疫细胞膜仿生载体还具有主动靶向和免疫逃逸的能力, 因此显示出作为靶向治疗肺部炎症和肺部肿瘤的载体的潜力^[63]。目前, 从巨噬细胞和中性粒细胞中收获的膜是肺靶向递送应用最多的免疫细胞膜。

2.5.1 巨噬细胞来源的膜仿生纳米载体

巨噬细胞是免疫细胞中数量最多的, 在免疫反应中起着至关重要的作用。使用巨噬细胞治疗炎症性疾病有几个优点^[64]。巨噬细胞是重要的抗原呈递细胞, 其表达抗原肽主要组织相容性复合体(MHC) 并触发随后的免疫反应^[65]。此外, 巨噬细胞可以通过巨噬细胞膜表面的相应受体与炎症部位的趋化因子(单核细胞化学引诱蛋白-1等) 之间的相互作用介导炎症反应^[66]。

有研究表明, 巨噬细胞通过其表达的整合素α4与在肿瘤细胞中过表达的血管细胞黏附分子-1 (VCAM-1) 结合, 巨噬细胞与肺肿瘤细胞具有密切的相互作用^[67]。巨噬细胞和肿瘤细胞之间的这种相互作用为使用巨噬细胞膜进行肺肿瘤靶向递送提供了潜在的应用。例如, 一种巨噬细胞膜修饰的依坦辛脂质体(etansine liposomes coated with macrophage membranes, MEL)(图 6), 可以靶向乳腺癌的肺转移部位^[68]。MEL是通过用巨噬细胞膜功能化依坦辛脂质体来赋予巨噬细胞的仿生功能而制造的。4T1细胞中MEL的细胞摄取信号比裸纳米粒高2.0倍, 这有效地验证了MEL中巨噬细胞膜修饰增强细胞摄取作用, 进而使药物更好地发挥抑制细胞活力的作用。当α4β1整合素标志物被封闭时, 与MEL组相比, 细胞摄取减少了25%。同时, 在体内分布实验中, 与裸纳米粒组相比, MEL组的肺中荧光信号强度增强了2.8倍, 并显著抑制了乳腺癌的肺转移。

除了肿瘤靶向能力外, 基于巨噬细胞“归巢”到炎症部位, 巨噬细胞仿生纳米载体进一步显示出抗炎的潜力。例如, 一种用于治疗急性肺损伤(acute lung injury, ALI) 的仿生抗炎纳米系统(MM-CEP/NLC)^[69]。MM-CEP/NLCs是用天然巨噬细胞膜(MMs) 包被的纳米结构脂质载体(NLCs) 制成, 以实现头孢菌素(CEP) 在肺部炎症中的有效积累, 从而达到治疗ALI的效果。鉴于巨噬细胞与COVID-19的进展密切相关, 有研究建立基于巨噬细胞仿生纳米载体的药物递送系统(PLGA@M) 用于COVID-19治疗^[70]。具体来说, PLGA@M由两部分组成, 一部分是用于包裹在纳米颗粒表面的巨噬细胞膜, 另一部分是用于载药的聚合物纳米颗粒(PLGA纳米颗粒)。由于巨噬细胞膜遗传的表面受体, PLGA@M可以伪装成迷你巨噬细胞, 竞争性地吸收多种促炎物质, 抑制巨噬细胞和中性粒细胞的活化, 最终缓解或阻止细胞因子风暴(CSS) 的进展。

2.5.2 中性粒细胞来源的膜仿生纳米载体

中性粒细胞作为最常见的白细胞, 参与体内各种炎症反应。炎症的暴发导致中性粒细胞的增加, 中性粒细胞是防御组织感染或损伤中病原体的第一线^[71]。

有研究利用中性粒细胞对炎症组织具有靶向特性, 通过从天然中性粒细胞中提取中性粒细胞膜而不影响其生物学特性, 装载司帕沙星(SPX) 的纳米颗粒被这些膜涂覆并伪装成中性粒细胞。与传统纳米药物相比, 中性粒细胞膜包被的纳米颗粒(NM-NP-SPX) 具有精准的靶向能力, 就像中性粒细胞在炎症暴发时可以在炎症部位积聚一样^[72]。此外, NM-NP-SPX可以延长循环时间, 具有控释特性。通过体内实验发现, 肺炎小鼠肺部血液、细菌和炎症细胞中代表性炎性细胞因子的浓度在注射NM-NP-SPX后的最初24 h显著降低, 这意味着NM-NP-SPX可以大大降低炎症患者的死亡风险。由于NM-NP-SPX对正常细胞的低细胞毒性, 受感染的肺部可以迅速恢复, 而不会对其他器官产生任何不良反应。近期, 也有研究表明中性粒细胞膜包被的脂质体负载酸性成纤维细胞生长因子(aFGF@NMLs), 可以选择性靶向发炎的肺, 并通过炎症抑制有效缓解脓毒症诱导的ALI^[73]。

除炎症靶向性外, 中性粒细胞膜也具有肿瘤靶向的特性。通过用炎性中性粒细胞膜包被可生物降解的PLGA NPs来设计中性粒细胞膜仿生纳米颗粒(NM-NPs)^[74]。通过负载第二代蛋白酶体抑制剂卡非佐米(CFZ), 制备的NM-NPs (NM-NP-CFZ) 具有预防新发转移和抑制已经形成的转移的治疗潜力(图 7)。在肺部几乎所有转移病变中都发现NM-NPs, 而PLGA NPs与转移部位的共渗性则要差得多, 靶向特性远不如NM-NPs。

2.6 细菌来源的膜仿生纳米载体

由于细菌膜和宿主细胞上的生物分子之间的相互识别是细菌黏附和进入靶细胞的第一步, 因此细菌膜已成为一种新的药物靶向递送载体^[75]。特别是, 从革兰阴性细菌中提取的细菌外膜囊泡(outer membrane vesicle, OMV), 其中含有高水平的免疫原性蛋白质和佐剂, 是激活病原体相关先天性和适应性免疫反应的替代选择^{[76, 77]}。

有研究利用高压驱动耐药肺炎克雷伯菌通过间隙, 诱导形成稳定的人工细菌仿生囊泡(bacterial biomimetic vesicles, BBV)^[78], 并且这些BBV几乎没有细菌细胞内蛋白或核酸, 产量很高(图 8)。BBV被树突状细胞有效地吸收以刺激其成熟。BBV作为克雷伯菌肺炎疫苗具有诱导细菌特异性体液和细胞免疫应答的双重功能, 以提高动物的存活率并抑制肺部炎症。

3 局限与展望

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上面讨论的所有膜仿生纳米载体, 都因其表面不同蛋白赋予纳米粒不同功能, 但是不同细胞来源的膜仿生纳米载体也有各自的不足之处。

RBC膜的主要弱点是其靶向能力差, 因此需对RBC膜涂层的纳米载体进行功能化修饰, 使其能精准靶向和渗透到靶细胞内。虽然PLT膜在治疗肺癌、肺转移及肺部炎症方面显示出免疫逃逸、肿瘤靶向和炎症靶向的优点, 但也存在需要克服的问题, PLT易于体外聚集, 其膜作为药物载体可能会导致不必要的血栓形成或出血, 这使得PLT膜包被的纳米颗粒的稳定性成为主要挑战。然而, 关于使用肿瘤细胞衍生膜诱导肿瘤发生的潜在风险的安全问题限制了这种递送策略的临床应用。MSC膜具有肿瘤和炎症靶向的优点, 但其较RBC在血液中的循环时间短、大量获取MSC相对不方便。使用免疫细胞衍生膜的主要限制是它们的免疫原性^[79]。因为在免疫细胞中表达的主要组织相容性复合体被其膜高概率遗传。OMV在大规模生产中具有易于体外扩增、易于生产功能化OMV等的优势。但是, OMV表面含有脂多糖和毒力因子可能会导致过度的免疫激活并导致生物安全问题^[80]。

除此之外, 较合成脂质体相比, 膜仿生纳米载体值得注意的是其自身复杂性。具体来说, 因为整个膜可以呈现数百种不同的分子, 有可能有一些蛋白质具有相同的功能, 或者一些意想不到的蛋白质为纳米粒的功能提供了重要作用。因此, 对这种复杂性可能需要在未来使用创新技术进行更多的探索, 以提供更深入的理解。同时, 膜仿生纳米载体表面蛋白质的分布可能限制了它们的化学灵活性, 并且仍然有必要系统地研究功能化技术如何影响这些纳米结构的仿生特性, 开发可重复且可扩展的分离、处理和修饰细胞膜的方法至关重要。

总的来说, 目前这些细胞膜仿生纳米粒离临床试验还有较远的距离, 需要研究人员解决问题克服挑战。

4 总结

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综上所述, 细胞来源的膜仿生纳米载体为肺部疾病的靶向治疗提供了一种高效、生物相容性好的策略, 在肺部疾病中显示出靶向递送的潜力(表 1), 具有良好的治疗效果。尽管膜仿生纳米载体递送策略仍有一些局限性或缺点仍有待解决，该策略为有效治疗肺部疾病开辟了一条全新的途径。

作者贡献: 白文静负责查阅文献和论文撰写; 熊淋和朱冷静负责撰写文章提纲; 李嘉欣和王雅施负责图表设计; 郭蓉和李曼参与论文修改; 何勤进行文章撰写指导。

利益冲突: 本文所有作者声明不存在利益冲突关系。

基金

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国家自然科学基金资助项目(82173761)
四川省科技项目(2022NSFSC0045)

参考文献

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2024年第59卷第10期

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doi: 10.16438/j.0513-4870.2023-1205

接收时间：2024-02-23
首发时间：2025-11-24
出版时间：2024-10-12

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收稿日期：2024-02-23
修回日期：2024-06-11

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国家自然科学基金资助项目(82173761)

四川省科技项目(2022NSFSC0045)

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1.四川大学华西药学院, 靶向药物及释药系统教育部重点实验室, 四川成都 610041

2.四川大学华西基础医学与法医学院, 四川成都 610041

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^*何勤, Tel: 86-28-85502532, E-mail: qinhe@scu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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