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细菌外膜囊泡在肿瘤治疗中的应用_CPHI制药在线
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href="/Products/list-htm-catid-25.html"> 中间体</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-25.html" target="_blank">中间体</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-26.html"> 医药中间体</a> <a href="/Products/list-htm-catid-27.html"> 农药中间体</a> <a href="/Products/list-htm-catid-28.html"> 其他中间体</a> <a href="/Products/list-htm-catid-355.html"> 精细化工</a> </div> <div class="list_list_img"> </div> </div> </li> <li> <span> <a href="/Products/list-htm-catid-29.html"> 生物制品</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-29.html" target="_blank">生物制品</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-30.html"> 试剂</a> <a href="/Products/list-htm-catid-63.html"> 生物技术服务</a> <a href="/Products/list-htm-catid-665.html"> 生物制剂</a> </div> <div class="list_list_img"> </div> </div> </li> <li> <span> <a href="/Products/list-htm-catid-75.html"> 天然提取物</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-75.html" target="_blank">天然提取物</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-76.html"> 植物提取物</a> <a href="/Products/list-htm-catid-77.html"> 动物提取物</a> <a href="/Products/list-htm-catid-646.html"> 微生物提取物</a> <a href="/Products/list-htm-catid-671.html"> 功能性食品原料</a> <a href="/Products/list-htm-catid-672.html"> 食品、饮料原料</a> <a href="/Products/list-htm-catid-673.html"> 保健品原料</a> <a href="/Products/list-htm-catid-674.html"> 膳食补充剂</a> <a href="/Products/list-htm-catid-675.html"> 中药原料</a> <a href="/Products/list-htm-catid-676.html"> 美容化妆品原料</a> <a href="/Products/list-htm-catid-940.html"> 其他天然提取物</a> </div> <div class="list_list_img"> </div> </div> </li> <li> <span> <a href="/Products/list-htm-catid-78.html"> 药品制剂</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-78.html" target="_blank">药品制剂</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-79.html"> 抗肿瘤制剂</a> <a href="/Products/list-htm-catid-80.html"> 抗寄生虫制剂</a> <a href="/Products/list-htm-catid-81.html"> 抗过敏用制剂</a> <a href="/Products/list-htm-catid-82.html"> 抗菌药与抗病毒药制剂</a> <a href="/Products/list-htm-catid-83.html"> 抗结核及麻风制剂</a> <a href="/Products/list-htm-catid-84.html"> 皮肤科制剂</a> <a href="/Products/list-htm-catid-85.html"> 五官科制剂</a> <a href="/Products/list-htm-catid-86.html"> 消化系统制剂</a> <a href="/Products/list-htm-catid-87.html"> 呼吸系统制剂</a> <a href="/Products/list-htm-catid-88.html"> 循环系统制剂</a> <a href="/Products/list-htm-catid-89.html"> 神经系统类制剂</a> <a href="/Products/list-htm-catid-90.html"> 血液系统药制剂</a> <a href="/Products/list-htm-catid-91.html"> 泌尿与生殖系统制剂</a> <a href="/Products/list-htm-catid-93.html"> 调节免疫功能制剂</a> <a href="/Products/list-htm-catid-94.html"> 调节水、电解质及酸碱平衡制剂</a> <a href="/Products/list-htm-catid-95.html"> 维生素、矿物质与氨基酸类制剂</a> <a href="/Products/list-htm-catid-96.html"> 酶类及其它生化制剂</a> <a href="/Products/list-htm-catid-97.html"> 解热镇痛类制剂</a> <a href="/Products/list-htm-catid-98.html"> 滋补营养药</a> <a href="/Products/list-htm-catid-99.html"> 有关激素类药</a> <a href="/Products/list-htm-catid-100.html"> 内分泌及代谢类制剂</a> <a href="/Products/list-htm-catid-101.html"> 清热解毒制剂</a> <a href="/Products/list-htm-catid-102.html"> 心脑血管类制剂</a> <a href="/Products/list-htm-catid-103.html"> 其它药品制剂</a> </div> <div class="list_list_img"> </div> </div> </li> <li> <span> <a href="/Products/list-htm-catid-104.html"> 药用辅料</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-104.html" target="_blank">药用辅料</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-105.html"> 赋形剂</a> <a href="/Products/list-htm-catid-106.html"> 崩解剂</a> <a href="/Products/list-htm-catid-107.html"> 润滑剂</a> <a href="/Products/list-htm-catid-108.html"> 助流剂</a> <a href="/Products/list-htm-catid-109.html"> 包衣材料</a> <a href="/Products/list-htm-catid-110.html"> 增塑剂</a> <a href="/Products/list-htm-catid-111.html"> 肠溶材料</a> <a href="/Products/list-htm-catid-112.html"> 表面活性剂</a> <a href="/Products/list-htm-catid-113.html"> 溶媒</a> <a href="/Products/list-htm-catid-114.html"> 抗氧剂</a> <a href="/Products/list-htm-catid-115.html"> 遮光剂</a> <a href="/Products/list-htm-catid-116.html"> 矫味剂</a> <a href="/Products/list-htm-catid-117.html"> 甜味剂</a> <a href="/Products/list-htm-catid-118.html"> 香精</a> <a href="/Products/list-htm-catid-119.html"> 着色剂</a> <a href="/Products/list-htm-catid-120.html"> 促透剂</a> <a href="/Products/list-htm-catid-121.html"> 助滤剂</a> <a href="/Products/list-htm-catid-122.html"> 澄清剂</a> <a href="/Products/list-htm-catid-123.html"> 防腐剂</a> <a href="/Products/list-htm-catid-124.html"> 稳定剂</a> <a href="/Products/list-htm-catid-125.html"> ＰＨ调节剂</a> <a href="/Products/list-htm-catid-126.html"> 催化剂</a> <a href="/Products/list-htm-catid-127.html"> 其他药用辅料</a> <a href="/Products/list-htm-catid-1039.html"> 推进剂</a> </div> <div class="list_list_img"> </div> 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</div> </div> <div class="newList_route"> <div class="content"> <a href="/">CPHI制药在线</a> <label>></label> <a href="/news/">资讯</a> <label>></label> <a href="/news/category/712">小泥沙</a> <label>></label> <a href="javascript:;">细菌外膜囊泡在肿瘤治疗中的应用</a> <label>></label> </div> </div> <div class="newsDetail"> <div class="content flex_between"> <input id="newsId" type="hidden" value="282633"/> <div class="newsDetail_article"> <div class="zixun-contain"> <h1 class="newsDetail_article_title">细菌外膜囊泡在肿瘤治疗中的应用</h1> <div class="newsDetail_article_create flex_between"> <div class="exam_news_createlocal"> 热门推荐： <a href="/news/search-htm-txtSearch-递送载体-hide_search-4.html">递送载体</a> <label>,</label> <a href="/news/search-htm-txtSearch-肿瘤治疗-hide_search-4.html">肿瘤治疗</a> <label>,</label> <a href="/news/search-htm-txtSearch-细菌外膜囊泡-hide_search-4.html">细菌外膜囊泡</a> <label>,</label> </div> <div class="exam_news_createtime" style="display: flex"> <div>作者：小泥沙  来源：CPHI制药在线</div>   2025-02-13</div> </div> <div class="news-brief"> 外膜囊泡（OMVs）是革兰氏阴性菌分泌的双层脂质纳米囊泡，含有多种成分，可用于细菌疫苗开发，在肿瘤治疗中能作为载体、直接杀伤肿瘤、激活免疫协助抗肿瘤，具有广阔应用前景。 </div> <div class="newsDetail_article_content"> <p style="text-align: center;"><img src="https://cimg.cphi.cn/img_Cphi_cn/image/2025/02/13/17_47_40.png" alt="细菌外膜囊泡在肿瘤治疗中的应用" width="400" height="233" /></p> <p>外膜囊泡(Outer membrane vesicles, OMVs)是由革兰氏阴性菌分泌的双层脂质纳米囊泡。OMVs 含有<strong><a href="https://www.cphi.cn/news/show-215129.html" target="_blank" rel="noopener">细菌</a></strong>衍生的多种成分，如脂质、蛋白质、核酸和其他小分子，还包括抗原病原体相关分子模式(Pathogen-associated molecular patterns, PAMPs)，这是疫苗的基本成分，基于此，天然 OMVs 或生物工程 OMVs 被开发为细菌疫苗，以对其亲本细菌产生强大的体液和细胞免疫应答。OMVs含有的多种生物分子，是细菌与细菌、环境和宿主等交流的重要介质，因此它们可能成为抗肿瘤的有效的方案。</p> <p><strong>OMVs 的结构成分</strong></p> <p>OMVs含有细菌多种衍生成分，主要包括脂质、蛋白质、核酸及其他小分子。OMVs 膜主要含有磷脂(Phospholipid, PL)和脂多糖(Lipopolysaccharide, LPS)，PL主要包括磷脂酰乙醇胺、磷脂酰甘油等，不同革兰氏阴性菌的OMVs 的磷脂含量有所不同。在大肠杆菌中，OMVs主要脂质为甘油磷脂、磷脂酰甘油、磷脂酰乙醇胺(Phosphatidyl ethanolamine, PE)和心磷脂；铜绿假单胞菌膜OMVs的主要成分为磷脂酰甘油；脑膜炎奈瑟菌的OMVs主要含有磷脂酰甘油和PE。LPS 是一种重要的PAMPs，在生物膜中发挥粘附功能，也是 OMVs 的主要组成部分。</p> <p>在OMVs中鉴定出的蛋白质可以分为三类：外膜的基本成分，腔内特定的货物蛋白，以及未知或污染的蛋白质。第一类属于外膜蛋白，如孔蛋白、较大运输系统的外膜蛋白部分、 锚定蛋白黏附蛋白、酶（如磷脂酶和蛋白酶），以及鞭毛或菌毛蛋白、补体调节蛋白、结合蛋白、不浊相关蛋白、转运体、离子通道蛋白等。第二类包括周质酶、细胞质酶以及一些毒力因子，如蛋白酶、肽酶、核酸酶、溶细胞素、霍乱毒素、空泡细胞毒素、细胞毒性膨胀毒素和脲酶等酶。最后一类蛋白质是常见的细胞质蛋白包括延伸因子、伴侣蛋白和热休克蛋白。 在OMVs 中也发现了许多细胞质和细胞内膜蛋白，这些蛋白被认为是来自培养物中裂解细胞的污染物。OMVs同时携带腔内和表面相关的DNA，此外RNA、质粒、噬菌体DNA和染色体 DNA在 OMVs中也有报道。研究认为核酸被OMVs 携带可能来自于环境中细胞的裂解残留物。此外，OMVs 还可以运输多种离子、群体感应信号和代谢物。</p> <p><strong>OMVs应用于肿瘤治疗</strong></p> <p>在抗肿瘤研究中，OMVs既能作为载体用于抗肿瘤药物的递送，也能作为免疫调节剂重塑肿瘤免疫微环境、激活机体自身免疫反应以协同化疗/PDT等疗法抑制肿瘤生长；在肿瘤疫苗领域，OMVs可同时作为疫苗纳米载体和佐剂以激起强效的肿瘤特异性免疫反应，而且OMVs自身也能通过诱导肿瘤细胞死亡、调节免疫等手段起到一定抑制肿瘤生长的作用。</p> <p><strong>1、OMVs的载体优势</strong></p> <p>易于修饰的特点及自身性质使OMVs被广泛作为抗肿瘤药物递送载体研究。首先，尺寸效应使OMVs本身就具有一定肿瘤靶向能力；其次，靶向修饰可进一步的增加OMVs对特定细胞的靶向性；最后，表面PAMPs分子与纳米级的粒径使得OMVs兼具佐剂性与淋巴滞留能力，这可以极大地协同抗原增强抗肿瘤免疫反应与表面修饰。</p> <p>对OMVs进行药物装载可分为分泌前装载与分泌后装载两类方法。分泌前加载是对细菌进行处理以得到封装有药物的OMVs，这种方法主要用于易变性的生物分子。例如，研究人员在细菌培养过程加入庆大霉素，利用细菌会通过OMVs排出有害物质的性质，得到了封装有庆大霉素的OMVs，而利用基因工程则可使OMVs高效加载蛋白质类药物。分泌后加载是将药物封装人已分离提纯的OMVs中，脂双层结构使OMVs既可封装疏水药物又可封装亲水药物。通过与药物共孵育，疏水性小分子药物可封装在OMVs膜内，同时带正电的小分子药物可利用静电吸附作用封装在OMVs膜上；而通过电穿孔、超声处理、物理挤出或渗透处理等方法可使OMVs封装亲水性药物分子。</p> <p>作为载体，OMVs可靶向肿瘤部位：OMVs表面富集的PAMPs使其易被血液循环中的中性粒细胞吞噬，而由于中性粒细胞具有炎性靶向能力，因此OMVs可利用中性粒细胞靶向炎性肿瘤组织。OMVs到达炎性肿瘤后，可通过中性粒细胞胞外陷阱（neutrophil extracellular traps，NETs）形成过程中被释放出来且不影响活性，这使得OMVs具有天然的肿瘤靶向能力。同时，20~250nm的粒径使OMVs可以自由循环至淋巴结，表面富集的PAMPs使其易于被DC摄取滞留淋巴，并诱导Th1型免疫反应。研究表明随插随显示的OMVs抗原展示平台在小鼠体内有明显的淋巴蓄积现象，激活了有效的抗肿瘤免疫反应。此外，OMVs可以通过毛囊途径和表皮渗透两种途径穿过角质层到达真皮层，这赋予了其作为透皮药物递送载体独特的优势。</p> <p><strong>2、OMVs对肿瘤的直接杀伤</strong></p> <p>在抗肿瘤研究中，OMVs自身就对肿瘤具有一定的杀伤效果。PAMPs的富集使OMVs可通过受体激活的死亡途径在细胞层面可诱导细胞发生焦亡或调亡。首先，有研究表明，OMVs通过内吞途径进人宿主细胞后可在早期内体阶段将LPS释放到胞质中，继而在GBPs的帮助下激活Caspase-11，引起细胞焦亡并释放炎性因子IL-1β，修饰后的LPS则不具有激活Caspase-11的能力。其次，细菌OMVs可诱导细胞线粒体膜电位降低，引发线粒体功能障碍，进而导致线粒体调亡、炎症小体激活，最终触发细胞凋亡。最后，致病菌OMVs可递送毒力因子诱导细胞死亡，例如：致病型大肠杆菌OMVs上携带的细胞质酶HlyF可通过阻断细胞自噬体与溶酶体的融合阻断自噬，激活非经典炎症小体途径，诱导细胞死亡。不过，细胞可通过多种途径抑制由OMVs诱导的细胞死亡。因此，OMVs诱导的细胞死亡受多种因素影响，包括OMVs的组分构成、PAMPs分子的相对浓度以及宿主细胞敏感度等。</p> <p>OMVs在活体层面也有一定的肿瘤抑制效果，这主要归功于OMVs对机体免疫系统的激活。首先，OMVs可以诱导肿瘤相关巨噬细胞(tumor-associated macrophage，TAM） 向促炎M1型巨噬细胞极化；其次，OMVs可招募包括NK细胞、T细胞在内的多种免疫细胞，这既能逆转肿瘤区域免疫抑制性的微环境，也能在肿瘤区域诱导干扰素（IFN-γ）的产生以介导肿瘤凋亡。然而，IFN-γ在介导肿瘤细胞调亡的同时会上调肿瘤细胞程序性死亡配体1（programmedcelldeath1 ligand1，PD-L1）的表达，这抑制了T细胞活性并最终降低了抗肿瘤效果。针对这个问题，研究人员通过基因工程化修饰得到了程序性死亡受体1(programmed cell death protein 1，PD-1）修饰的OMVs，在保留OMVs肿瘤杀伤能力的同时通过对肿瘤细胞表面PD-L1的封闭解除了肿瘤细胞对T细胞的功能抑制，显著提高了肿瘤抑制效果。类似的，通过基因工程得到的表面表达CD47抗体的OMVs不仅能封闭肿瘤表面CD47分子以解除其对巨噬细胞的吞噬抑制，还能作为桥梁连接巨噬细胞与肿瘤细胞以增强吞噬，该工程化的OMVCD47nb在小鼠体内重塑了肿瘤微环境且激活了肿瘤特异性免疫反应，在有效抑制肿瘤生长的同时诱导了对肿瘤的长期免疫记忆。</p> <p><strong>3、OMVs激活免疫协助增强抗肿瘤效果</strong></p> <p>OMVs对机体免疫系统的调节作用使其在抗肿瘤研究中大有可为。首先，OMVs对免疫细胞的强烈刺激可对免疫抑制性的肿瘤微环境进行重编程，这可增强化疗、光动力等对肿瘤的抑制效果。其次，OMVs的佐剂性及淋巴靶向性使其在肿瘤疫苗的应用中有着广泛应用前景。因此，OMVs主要作为递送载体、免疫调节剂、佐剂等应用于临床前抗肿瘤研究。</p> <p>在肿瘤治疗中，OMVs不仅可作为纳米递送载体增加抗肿瘤药物的利用率并降低药物副作用，还可以作为免疫调节剂激活机体免疫反应以协同增强化疗、PDT等抗肿瘤疗法的疗效。早在2014年，研究人员利用基因工程化的接有肿瘤靶向肽的减毒OMVs向肿瘤部位递送了小干扰RNA（small interfering RNA，siRNA），有效抑制了肿瘤生长。此后，OMVs被广泛用于抗肿瘤药物的递送。例如，载有光敏剂二氢卟吩e6（chlorine6，Ce6）和化疗药阿霉素（doxorubicin，DOX）的OMVs作为治疗平台，通过光动力、化疗与免疫疗法的有机协同实现了对小鼠三阴性乳腺肿瘤的完全抑制，并成功防止了肿瘤转移的发生。负载黑色素的OMVs有着良好的光热转换效率，其不仅可在近红外激光的照射下对肿瘤进行局部加热以杀死肿瘤，还可利用多光谱光声断层扫描技术（multispectral optoacoustic tomography，MSOT） 对肿瘤组织进行光声成像。</p> <p>在肿瘤疫苗研究中，OMVs同时作为疫苗纳米载体与免疫佐剂来增强由针对肿瘤抗原的特异性免疫反应。作为载体，工程化的OMVs既可以快速捕获多种肿瘤抗原，又可以靶向淋巴结并增强DC对抗原的摄取，同时OMVs能作为佐剂进一步增强肿瘤特异性免疫反应，强效的免疫反应消除了小鼠皮下肿瘤并抑制了肿瘤的转移。类似的，利用OMVs向DC递送抗原mRNA能引起有效的抗肿瘤免疫反应，成功实现了对肿瘤的抑制并诱导了长期免疫记忆的产生。然而由佐剂诱导的DC快速成熟会导致其摄取能力降低，这种现象被称为成熟诱导的摄取阻塞(maturation-induced uptake obstruction，MUO）。对此，研究人员通过在OMVs修饰上葡萄球菌蛋白A的结构域B（domain Bof staphylococcal protein A）以结合αDEC205抗体的Fc端，而αDEC205抗体的Fab端与DC表面DEC205（CD205，一种具有抗原呈递功能的内吞受体）的结合使OMV-DEC能通过异位摄取途径突破MUO的限制。因此，DC对OMV-DEC表现出比OMVs更强的摄取能力，这增强了OMV-DEC对抗原的呈递能力，激活了更强的抗肿瘤免疫反应，成功抑制了黑色素瘤的生长与转移。</p> <p>作为细菌分泌物，OMVs可由肠道细菌原位产生，因此，研究人员开发了一种阿拉伯糖诱导型基因工程化大肠杆菌作为口服型肿瘤疫苗。大肠杆菌在小鼠肠道原位产生负载肿瘤抗原的OMVs，其可穿过肠上皮细胞屏障，刺激DC成熟，并进一步激活肿瘤特异性免疫反应以杀伤肿瘤细胞。在小鼠模型中，该疫苗不仅实现了对肿瘤的抑制，原位产生的方式还使其避免了分离提纯的繁琐步骤，有效降低了生产成本。而为了实现个性化治疗，可将OMVs与肿瘤细胞膜或肿瘤外泌体融合，得到的杂化囊泡作为个性化肿瘤疫苗能诱导强烈的适应性免疫反应，提高小鼠生存率并提供对肿瘤的长期防护。进一步的，OMV-Mal可在肿瘤原位捕获PTT后释放的肿瘤抗原，并将之递送至DC以引发肿瘤特异性免疫反应。这种策略不仅通过增强抗原摄取、刺激DC成熟等手段增强了免疫反应，还实现了免疫疗法与PDT、PTT、化疗等治疗方法的协同。</p> <p>OMVs在肿瘤领域中具有多重功能。它们不仅促进肿瘤生长和转移，还调节肿瘤微环境，抑制<a href="https://www.cphi.cn/news/show-281942.html" target="_blank" rel="noopener"><strong>肿瘤</strong></a>的发展。OMVs 中携带的生物标志物还可以作为肿瘤的诊断标志，有助于肿瘤的早期监测。此外，OMVs作为药物载体，可有效传递抗肿瘤药物到肿瘤部位，提高治疗效果，因此具有广阔的应用前景。</p> <p><strong>参考资料</strong></p> <p>[1]毛露珈,史恩宇,王瀚平,等.细菌外膜囊泡在抗肿瘤治疗方面的研究进展[J].中国生物工程杂志,2022,42(05):100-105.</p> <p>[2]王云锋,庄婉茹,马宪彬,等.细菌外膜囊泡应用于肿瘤治疗[J].生物化学与生物物理进展,2024,51(02):309-327.</p> <p><strong>作者简介：</strong>小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。</p> </div> <div class="newsDetail_article_others"> <div class="yuanchuang"> <label>版权所有，未经允许，不得转载。</label> </div> </div> </div> <div class="xiangguantuijian" style="margin-top: 30px;border-bottom: none;"> <div class="xiangguantuijian_title"> <div class="tuijian_title_left"> <div class="tuijian_title_type"></div> <div class="tuijian_title_text">相关文章</div> </div> </div> <div class="about_article_list"> </div> </div> </div> <div class="newsDetail_info"> <div class="zhuanlaninfo_box"> <div class="zhuanlaninfo_box_info"> <a 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