药学学报

Vesicle source	Application	Synergistic immune pathway	Ref.
Ginseng	Inhibit melanoma growth	Activated TLR4/MyD88 signaling pathway; polarized M1-like macrophages; altered the tumor immune microenvironment; elevated reactive oxygen species (ROS)	[44]
Platycodon grandiflorum	Regulate inflammation and repair lung damage	Increased the expression of anti-inflammatory factors; inhibited the release of inflammatory factors; controlled the glycolysis and lipid metabolism pathways of macrophages	[45]
Catharanthus roseus	Inhibit tumor growth	Promoting the secretion of cytokines TNF-α and IL-2; enhanced phagocytic function; promoted macrophage polarization and lymphocyte proliferation; enhanced the immune responses through the TNF-α/NF-κB/PU.1 axis	[47]
Artemisia annua	Inhibit lung cancer growth	Activated cGAS-STING pathway of macrophage by delivery of mitochondrial DNA (mtDNA) drives the transition of TAMs to an antitumor phenotype	[48]
Garlic	Enhance the efficacy of anti-PD-L1 immunotherapy	Activated intestinal γδ T cells to release IFN-γ; modified the tumor microenvironment; worked with PD-L1 inhibitors to improve immunity against tumors	[49]
Brucea javanica	Inhibit the growth of breast cancer	Inhibited the growth of breast cancer, metastasis and angiogenesis through the PI3K/Akt/mTOR signaling pathway	[51]
Glycyrrhiza uralensis Fisch roots	Inhibit the growth of melanoma	Inhibited tumor growth and enhanced the anti-tumor immune responses by loading the STING agonist DMXAA and surface-modifying with PD-L1 antibodies	[52]
Ginseng	Repair inflammatory bowel disease (IBD)	Activated autophagy; polarized M1-like macrophages; directly acts on intestinal epithelial cells through the IKK/IκB/NF-κB signaling pathway; restored the intestinal barrier	[53]
Aristolochia	Inhibit the proliferation of liver cancer cells	Regulated amino acid metabolism and glycerophospholipid metabolism in tumor cells; reduced lipid synthesis; induced ROS production and apoptosis; enhanced recognition of immune cells	[54]
Camellia sinensis	Inhibit breast cancer growth and metastasis	Promoted ROS production; killed tumor cells; regulated intestinal flora; enhanced systemic immune responses	[55]

Vesicle source	Application	Synergistic immune pathway	Ref.
Ginseng	Inhibit melanoma growth	Activated TLR4/MyD88 signaling pathway; polarized M1-like macrophages; altered the tumor immune microenvironment; elevated reactive oxygen species (ROS)	[44]
Platycodon grandiflorum	Regulate inflammation and repair lung damage	Increased the expression of anti-inflammatory factors; inhibited the release of inflammatory factors; controlled the glycolysis and lipid metabolism pathways of macrophages	[45]
Catharanthus roseus	Inhibit tumor growth	Promoting the secretion of cytokines TNF-α and IL-2; enhanced phagocytic function; promoted macrophage polarization and lymphocyte proliferation; enhanced the immune responses through the TNF-α/NF-κB/PU.1 axis	[47]
Artemisia annua	Inhibit lung cancer growth	Activated cGAS-STING pathway of macrophage by delivery of mitochondrial DNA (mtDNA) drives the transition of TAMs to an antitumor phenotype	[48]
Garlic	Enhance the efficacy of anti-PD-L1 immunotherapy	Activated intestinal γδ T cells to release IFN-γ; modified the tumor microenvironment; worked with PD-L1 inhibitors to improve immunity against tumors	[49]
Brucea javanica	Inhibit the growth of breast cancer	Inhibited the growth of breast cancer, metastasis and angiogenesis through the PI3K/Akt/mTOR signaling pathway	[51]
Glycyrrhiza uralensis Fisch roots	Inhibit the growth of melanoma	Inhibited tumor growth and enhanced the anti-tumor immune responses by loading the STING agonist DMXAA and surface-modifying with PD-L1 antibodies	[52]
Ginseng	Repair inflammatory bowel disease (IBD)	Activated autophagy; polarized M1-like macrophages; directly acts on intestinal epithelial cells through the IKK/IκB/NF-κB signaling pathway; restored the intestinal barrier	[53]
Aristolochia	Inhibit the proliferation of liver cancer cells	Regulated amino acid metabolism and glycerophospholipid metabolism in tumor cells; reduced lipid synthesis; induced ROS production and apoptosis; enhanced recognition of immune cells	[54]
Camellia sinensis	Inhibit breast cancer growth and metastasis	Promoted ROS production; killed tumor cells; regulated intestinal flora; enhanced systemic immune responses	[55]

中草药囊泡: 调控代谢增效免疫的肿瘤治疗新策略

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王竞凰 ¹^,² , 易志文 ¹^,² , 封宽瀚 ¹^,² , 陈富财 ¹^,² , 狄留庆 ¹^,² , 王若宁 ¹^,²^,^*

药学学报 | 综述 2025,60(9): 2730-2739

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药学学报 |综述 2025 , 60 (9) : 2730 -2739

中草药囊泡: 调控代谢增效免疫的肿瘤治疗新策略

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王竞凰¹^,², 易志文¹^,², 封宽瀚¹^,², 陈富财¹^,², 狄留庆¹^,², 王若宁¹^,²^,^*

作者信息

¹南京中医药大学药学院, 江苏南京 210023

²江苏省中药高效给药系统工程技术研究中心, 江苏南京 210023

通讯作者:

王若宁, E-mail: ruoningw@njucm.edu.cn

作者简介:

作者贡献:

王竞凰具体完成文章撰写; 易志文完成文献检索和筛选; 封宽瀚完成文章的修改; 陈富财确定文章方向及内容组成; 王若宁和狄留庆对文章撰写质量进行把关和审校。

Chinese herbal medicine-derived extracellular vesicles: a new strategy for regulating metabolism and synergistic immunity

Jing-huang WANG¹^,², Zhi-wen YI¹^,², Kuan-han FENG¹^,², Fu-cai CHEN¹^,², Liu-qing DI¹^,², Ruo-ning WANG¹^,²^,^*

Affiliations

¹School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

²Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System, Nanjing 210023, China

出版时间: 2025-09-12 doi: 10.16438/j.0513-4870.2025-0678

文章导航

摘要

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相较于正常细胞, 肿瘤细胞展现出独特的代谢特征。针对肿瘤能量代谢特点制定的治疗策略, 旨在从根源上阻断肿瘤细胞的能量与物质供给, 重塑免疫抑制微环境, 为免疫细胞浸润并发挥功能创造有利条件。近年来, 源自中草药的天然囊泡凭借其独特的代谢调控能力与靶向特性, 在肿瘤研究领域备受瞩目。这类囊泡不仅能够精准递送多种活性分子成分, 还可通过重新编程肿瘤微环境中细胞的代谢过程, 打破免疫抑制的僵局, 进而增强抗肿瘤免疫应答。本文综述了中草药囊泡在代谢调控方面的作用机制, 及其增效免疫治疗的最新研究进展, 并对其临床转化潜力与未来研究方向进行展望。

关键词

中草药囊泡 / 代谢调控 / 免疫协同 / 肿瘤微环境 / 多组分递送

Abstract

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Compared with normal cells, tumor cells exhibit unique metabolic characteristics. The therapeutic strategies formulated based on the energy metabolic features of tumors aim to block the energy and material supply of tumor cells at the source, remodel the immunosuppressive tumor microenvironment (TME), and create favorable conditions for immune cell infiltration and function. In recent years, Chinese herbal medicine-derived extracellular vesicles have attracted attention due to their unique metabolic regulatory capabilities and targeting properties. These extracellular vesicles can not only precisely deliver multi-component active molecules but also reprogram the metabolic processes in the tumor microenvironment, reverse immunosuppressive conditions, and thereby enhance antitumor immune responses. This review systematically summarizes the metabolic regulatory mechanisms of TCM-derived vesicles and their synergistic effects in immunotherapy, and looks forward to their clinical transformation potential and future research directions.

Key words

Chinese herbal medicine-derived extracellular vesicle / metabolic regulation / immune synergy / tumor microenvironment / multicomponent delivery

引用本文

王竞凰, 易志文, 封宽瀚, 陈富财, 狄留庆, 王若宁. 中草药囊泡: 调控代谢增效免疫的肿瘤治疗新策略. 药学学报, 2025 , 60 (9) : 2730 -2739 . DOI: 10.16438/j.0513-4870.2025-0678

Jing-huang WANG, Zhi-wen YI, Kuan-han FENG, Fu-cai CHEN, Liu-qing DI, Ruo-ning WANG. Chinese herbal medicine-derived extracellular vesicles: a new strategy for regulating metabolism and synergistic immunity[J]. Acta Pharmaceutica Sinica, 2025 , 60 (9) : 2730 -2739 . DOI: 10.16438/j.0513-4870.2025-0678

正文

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在肿瘤的生长与演进历程中, 肿瘤细胞会经历一系列代谢功能的显著改变, 这一现象被称作代谢重编程。肿瘤细胞借助代谢重编程机制, 实现了对营养物质的高效利用, 从而为其增殖提供了坚实的能量与物质基础, 同时助力它们适应肿瘤微环境中诸如低氧、营养匮乏等严苛的生存条件^[1]。具体而言, 肿瘤细胞的代谢变化主要体现在糖代谢增强(Warburg效应)、氨基酸代谢改变、脂肪酸合成与氧化的平衡失调以及氧化应激增加等方面。这些代谢方面的改变不仅为肿瘤细胞实现快速增殖提供了不可或缺的能量供给以及用于生物合成的关键原料, 还通过代谢产物塑造免疫抑制的微环境, 助力其逃避免疫系统监视与攻击^[2]。

调节肿瘤微环境的能量代谢, 已成为癌症治疗领域的一项关键策略。对肿瘤细胞的代谢重编程进程加以抑制, 可达成有效抑制肿瘤细胞生长与增殖的效果。此外, 这种干预方式还能改善免疫细胞在肿瘤微环境中的浸润能力, 强化其功能, 以此激发机体呈现出更强的抗肿瘤免疫应答能力^[3]。例如, 抑制糖酵解能减少乳酸产生, 改善酸性的肿瘤微环境, 提高免疫细胞活性^[4]; 调控谷氨酰胺代谢则有助于减少免疫抑制性代谢产物的堆积, 强化免疫细胞的功能^[5]; 调节脂肪酸代谢和抗氧化应激反应也可以优化肿瘤微环境, 增强免疫治疗的效果^[6]。因此, 代谢重编程不仅是肿瘤细胞适应快速增殖和恶劣微环境的关键机制, 也是癌症治疗中的重要靶点^[7]。

近年来, 随着细胞外囊泡(extracellular vesicles, EVs) 研究领域的不断拓展与深化, 一种源自天然的药物递送载体——中草药囊泡, 逐渐走进了人们的视野。中草药囊泡是从药用植物中提取的纳米级膜结构, 具有独特的生物活性和潜在的医学应用价值。这些囊泡不仅保留了母体植物的功能性成分, 如miRNA、代谢物和蛋白质, 实现多组分协同递送; 同时, 它们还具有天然靶向性和低免疫原性的特性, 这使得中草药囊泡在药物递送领域展现出巨大的优势^[8]。作为一种新兴的治疗手段, 中草药囊泡因其独特的特性在调节肿瘤微环境代谢方面展现出巨大的应用潜力。它能够特异性识别并作用于肿瘤细胞或特定的免疫细胞, 以此增强药物递送的精准性, 显著减少对正常组织产生的损害, 并且还能实现多组分的协同治疗^[9]。

伴随生物医学技术的迅猛演进, 免疫治疗在癌症治疗领域脱颖而出, 成为具有里程碑意义的重大突破, 为大量癌症患者带来了全新的治疗契机与希望曙光。而基于中草药来源的天然囊泡, 因其独特的代谢调控能力与靶向性, 在增强免疫治疗疗效方面显示出巨大潜力。这些天然囊泡不仅能够精准递送多组分活性分子, 还可通过重编程肿瘤微环境中的代谢进程, 克服免疫抑制的困境障碍, 进而显著提升抗肿瘤免疫应答效率。

本文梳理了当下中草药囊泡在调控肿瘤细胞代谢领域的研究进展。深入探讨了借助中草药囊泡中所含的活性物质, 增强其与免疫疗法协同治疗的可能性, 旨在达成通过代谢调控来强化免疫治疗效果的目的。此外, 还进一步剖析了这种治疗方式所具备的优势以及面临的挑战, 期望能为后续相关研究及临床应用提供有价值的参考依据。

1　中草药囊泡概述

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近年来, 从药用植物中提取的纳米级膜结构因其独特的生物活性和潜在的医学应用价值而受到广泛关注。这些物质主要来源于一些常见的药用植物, 如人参、黄芪和丹参等, 具有脂质双层结构, 尺寸通常在30~500 nm之间, 这一尺寸使其能够高效地穿透细胞膜, 实现药物的精准递送。中草药囊泡不仅保留了母体植物的功能性成分, 如miRNA、代谢物和蛋白质, 还具有天然靶向性和低免疫原性的特性^[10]。这种天然靶向性意味着它们能够特异性地识别并作用于特定的细胞类型, 从而提高治疗效果并减少对正常组织的损伤, 而低免疫原性则确保了它们在体内应用时的安全性和耐受性, 降低了引发机体排斥的风险。

无论是新鲜的中草药植株及其制品, 还是经过干燥处理后的中药材, 均能作为提取中草药囊泡的原料。对于新鲜植物类中药, 经过简易预处理后, 可直接采用榨汁或浸泡的方式提取(例如巴戟天); 而干燥后的中药材, 则需通过煎煮来获取有效成分(如黄芪、金银花、甘草以及红景天等)。随后, 利用适宜的技术手段对所得提取液进行进一步分离与富集, 即可获得中草药囊泡^[11]。目前, 多数研究倾向于结合两种或多种方法, 旨在提升提取效率并优化囊泡的纯度。

中草药囊泡的制备方法主要包括离心法、挤出法、超声处理法、冻融法、电穿孔法及pH梯度法等物理化学技术, 亦可采用浸泡法或煎煮法等传统提取工艺。方法的选择需综合考量药材特性、应用场景与实验需求^[12]。其中, 差速离心法作为基础提取技术, 将新鲜或干燥药材经缓冲液匀浆后, 依次进行梯度离心^[13]。然而, 由于某些药用植物细胞具有细胞壁和机械组织, 如人参和田七等块茎类药用植物, 提取时可能需要使用纤维素酶解等辅助手段, 以提高囊泡提取效率和产量。最终产物需通过粒径分析、形态学表及标志物检测进行质量控制, 所有关键参数(离心条件、酶解浓度等) 依据具体药材特性优化。

中草药囊泡富含多种药理活性分子、核酸、蛋白质及脂质且具有独特的形态与组成特性^[14]。在这些成分中, 小分子化合物是中草药囊泡发挥药效的核心物质。以生姜来源囊泡为例, 其中含有6-姜烯酚和6-姜辣素等^[15]、柚皮苷和柚皮素是西柚来源囊泡中的代表小分子活性物质^[16]。这些小分子化合物展现出调控细胞内信号通路的潜能, 进而干预细胞的代谢活动。此外, 中草药囊泡内还富含多种核酸类物质, 例如miRNA与siRNA等。这些核酸成分在植物的生长发育、免疫响应机制^{[17, 18]}及应对胁迫反应^{[19, 20]}的过程中, 均发挥着关键的调控作用, 并且与抗炎、抗肿瘤效应有着密切的联系。例如, 生姜来源的囊泡中包含ath-miR167a, 有缓解肠道炎症的作用^[15]; 紫苏叶囊泡通过携带pab-miR396a-5p, 靶向抑制HSP90并下调IL-17通路, 有缓解银屑病的治疗效果^[21]。

中草药囊泡蛋白质丰富, 兼具分子标志与独特生物活性赋予功能。例如, 葡萄囊泡可检测出水通道蛋白^[22]等, 在物质运输和细胞间通讯中作用显著。脂质成分是中草药囊泡结构的重要组成部分, 例如生姜囊泡中含有磷脂酸、磷脂酰甘油等脂质成分^[15], 蒲公英与黄芪囊泡中均含有三酰甘油、神经酰胺等类似的脂质成分^[23], 这些脂质成分参与细胞间信号传递, 调节膜流动性, 进而影响细胞代谢。

2　中草药囊泡调控肿瘤细胞代谢

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肿瘤细胞的代谢变化是肿瘤生物学中的一个关键特征, 这些变化不仅支持其快速增殖, 还影响肿瘤微环境(tumor microenvironment, TME) 和免疫反应。近年肿瘤代谢研究深化, 代谢重编程在肿瘤起始、进展与转移中的作用愈发凸显。肿瘤细胞正是借助代谢重编程机制, 适应不利的微环境, 逃避免疫监视, 并促进其快速增殖和转移(图1)。因此, 肿瘤代谢变化不仅是一个重要的研究领域, 也是一个极具潜力的治疗突破口。中草药囊泡作为中草药中的新型生物活性组分, 因其独特的代谢调控能力, 在肿瘤治疗中展现出广阔的应用前景。

2.1　糖代谢

在糖代谢途径上, 肿瘤细胞相较于正常细胞展现出了显著差异。通常在有氧条件下, 正常细胞会优先启动有氧糖酵解途径, 葡萄糖于细胞质基质糖酵解成丙酮酸, 丙酮酸入线粒体基质参与三羧酸循环, 经系列反应生成大量ATP供能^[24]。然而, 即便处于有氧环境, 肿瘤细胞仍倾向以无氧糖酵解方式分解葡萄糖, 产物为乳酸, 该独特代谢现象被定义为Warburg效应^[25], 但在这个过程中的能量产生效率并不高。在肿瘤细胞代谢特性里, 葡萄糖摄取和利用明显异常。肿瘤细胞上调葡萄糖转运蛋白1 (glucose transporter 1, GLUT1) 表达, 构建高效摄取系统, 大量摄取葡萄糖以支撑快速增殖。另外, 肿瘤细胞里多种重要代谢酶(己糖激酶2、甘油醛-3-磷酸脱氢酶等) 表达明显升高。这些酶在糖酵解途径中是核心催化剂, 过表达能加快酶促反应、优化代谢调控, 加速糖酵解, 为肿瘤生长、存活和侵袭转移等提供代谢支持^[26]。鉴于肿瘤细胞中独特的Warburg效应, 以糖酵解为干预靶点的抗肿瘤代谢治疗策略, 为肿瘤治疗开辟了可行新途径。

中草药囊泡内所含的某些内源性抗肿瘤成分, 能够经由特定的潜在靶点或信号通路, 对糖代谢过程实施调控作用。例如, 姜黄囊泡中的内源性活性成分姜黄素^[27]凭借多靶点机制可以抑制糖酵解, 下调GLUT4、HK2、PFKFB3蛋白与mRNA表达, 从转录、翻译双途径抑制糖酵解相关酶合成及功能, 显著发挥抗肿瘤作用^{[28, 29]}。丹参囊泡中的内源性二萜类活性物质丹参酮II_A^[30]能调节Akt/mTOR信号通路里的相关成员和缺氧诱导因子-1α (HIF-1α) 的活性, 进而影响GLUT1、PKM2及HK2表达, 显著下调糖代谢相关酶的表达, 抑制糖酵解代谢途径^[31]。

2.2　脂质代谢

与正常细胞不同, 肿瘤细胞的脂质代谢表现出异常活跃的特征。即使胞内脂质浓度处于正常生理范围, 肿瘤细胞仍持续维持高水平的脂质合成。这一现象可能与肿瘤细胞中脂质合成调控通路的异常激活有关, 例如胆固醇调节元件结合蛋白(sterol-regulatory element binding proteins, SREBPs) 信号通路在肿瘤细胞中可能存在过度活化, 导致脂质合成不受正常负反馈调节的抑制。此外, 肿瘤细胞会将多余的脂质以脂滴的形式储存于细胞质中。这些脂滴在肿瘤细胞面临能量供应不足的“饥饿”状态时, 可作为能量储备, 脂质分解后释放游离脂肪酸, 进入线粒体β-氧化, 为肿瘤细胞生存和增殖提供能量^{[32, 33]}。肿瘤细胞通过脂质代谢重编程策略, 显著提升脂肪酸从头合成速率并增强外源性脂肪酸的摄取能力, 从而满足其快速增殖过程中对脂质的大量需求。肿瘤细胞利用脂肪酸氧化机制, 把脂肪酸分解转化为能量物质, 从而维持肿瘤的进展态势, 并助力肿瘤细胞获得对放疗和化疗的耐药性。

中草药囊泡或其有效内源性成分可靶向作用于肿瘤细胞的脂质代谢环节, 通过抑制脂质合成通路相关分子或调控脂质代谢相关蛋白的表达与功能, 抑制肿瘤细胞内旺盛的脂质代谢活动。以茯苓囊泡(Poria cocos-derived exosome-like nanovesicles, PCELNs) 为例, 动物实验等研究显示, 该囊泡能够调节血脂水平, 改善氧化应激和能量代谢紊乱^[34]。姜黄囊泡中内源性活性成分姜黄素^[27]在脂代谢调节领域发挥着重要作用, 它借助激活PPARα通路等途径, 实现对血脂的精准调节, 加速脂肪酸的氧化代谢, 抑制脂肪细胞的分化与增殖, 进而有效纠正脂代谢紊乱的病理状态^[35]。葛根囊泡中的内源性活性成分葛根素^[36]能抑制脂肪酸合成酶和固醇调节元件结合蛋白-1c (SREBP-1c) 表达, 阻止肝细胞异常产脂行为, 改善肝脏脂质代谢和氧化应激^[37]。

2.3　氨基酸代谢

氨基酸在生物体内主要承担着蛋白质合成的基础性功能, 是构建生命大分子蛋白质的基本单元。同时, 部分氨基酸还可通过氧化分解途径释放能量, 为细胞的各种生理活动提供动力支持; 此外, 它们亦能参与到叶酸循环等重要代谢通路中, 在核酸合成、一碳代谢等关键生理过程中发挥重要的调控作用^[38]。正常细胞摄取氨基酸主要通过细胞表面的氨基酸转运蛋白, 其摄取量相对稳定, 能满足自身生长和维持功能的需求。肿瘤细胞上调氨基酸转运蛋白表达促氨基酸摄取^[39], 特别是上调某些氨基酸转运蛋白(如SLC6A14) 来满足其快速增殖的需求^[38]。肿瘤细胞需要大量氨基酸来合成蛋白质, 特别是谷氨酰胺代谢重编程在维持肿瘤细胞能量稳态、活性氧(reactive oxygen species, ROS) 平衡和mTOR的持续激活方面发挥重要作用^[40]。

中草药囊泡或其有效成分可干预肿瘤细胞的代谢途径, 通过调节肿瘤细胞表面的氨基酸转运蛋白表达, 减少肿瘤细胞对氨基酸的摄取。黄芪囊泡(Astragalus Radix vesicles-like nanoparticles, AR-VLNs) 通过修复肠道黏膜屏障和调节睡眠剥夺小鼠的氨基酸代谢来改善能量代谢紊乱, AR-VLNs激活肠道氨基酸转运蛋白(如SLC6A19、SLC38A5), 增强肠道对氨基酸的重吸收, 同时通过miRNA靶向抑制氨基酸降解酶(如丝氨酸脱水酶), 减少氨基酸无效分解^[41]。

综上所述, 肿瘤细胞的代谢重编程是一个极具潜力的治疗突破口, 中草药囊泡及其有效成分通过调控肿瘤细胞的代谢过程, 展现出良好的抗肿瘤潜力。中草药囊泡是中草药经过特殊处理后形成的微小囊状结构, 其活性组分与母体中草药的活性组分相同, 而中草药囊泡的提取与分离实现了对中草药多组分的有效富集与整合, 在保留中草药原有药效的同时, 凭借纳米级特性提升了药物传递的精准性和有效性。由此可见, 中草药囊泡不仅具备作为潜在抗肿瘤药物的独立价值, 能与现有疗法联合, 通过协同作用增强疗效, 为肿瘤治疗带来新希望。

3　中草药囊泡调节肿瘤免疫治疗

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中药囊泡在抗肿瘤免疫治疗中具有独特的优势和特点。与传统抗肿瘤免疫药物相比, 中药囊泡作为天然来源的纳米载体, 具有多靶点协同作用, 能够全面调控免疫细胞功能、细胞因子和信号通路^[42], 增强免疫反应。其天然来源和良好的生物相容性使其安全性更高, 毒副作用更小。同时, 中药囊泡具有主动靶向性, 能够精准递送药物至肿瘤部位, 调节免疫细胞极化和改善肿瘤微环境。此外, 中药囊泡还具有联合治疗潜力, 可与免疫检查点抑制剂或其他抗肿瘤治疗方法协同增效。这些特点使中药囊泡在抗肿瘤治疗中展现出广阔的应用前景。

3.1　调节免疫细胞功能

中草药囊泡在重塑肿瘤免疫微环境方面表现出显著的潜力, 能够通过调节微环境中的免疫细胞功能来改善病理进程。其核心作用机制之一在于诱导肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs) 发生表型转换, 即从具有促肿瘤作用的M2表型转变为具备抗肿瘤功能的M1表型, 进而强化机体的抗肿瘤免疫应答^[43]。Cao等^[44]研究表明, 人参囊泡中含多种代谢产物, 可介导细胞间信号传递, 借助TLR4和MyD88信号通路起效, 逆转肿瘤免疫微环境, 使得肿瘤相关巨噬细胞从M2型极化为M1型, 并产生大量活性氧, 促进小鼠黑色素瘤细胞凋亡。Fu等^[45]研究发现, 桔梗囊泡具有将巨噬细胞从促癌M2型逆转为抑癌M1型的能力, 进而解除免疫抑制状态, 提升微环境内T淋巴细胞对肿瘤细胞的杀伤毒性, 形成多维度的抗癌效应。Wu等^[36]从葛根(Pueraria lobata) 中提取得到了葛根囊泡, 并研究了其对巨噬细胞极化的影响。研究发现, 葛根来源的外泌体能够被巨噬细胞摄取, 并显著促进M1型巨噬细胞向抗炎的M2型极化, 表现为降低促炎细胞因子(如IL-6、IL-1β、TNF-α等) 的表达, 同时提高抗炎细胞因子(如IL-10、YM1、CD206等) 的表达水平。这些结果表明, 葛根囊泡通过激活外泌体和调节巨噬细胞极化来发挥和增强抗炎作用。

3.2　调节细胞因子

调节细胞因子分泌在免疫调节中具有重要意义, 不仅能够维持免疫平衡, 调节免疫细胞功能, 增强抗感染和抗肿瘤能力, 还能有效控制炎症反应, 中草药来源囊泡因其独特的免疫调节能力, 调节细胞因子分泌, 增强免疫反应治疗肿瘤。Han等^[46]的研究揭示, 源自人参囊泡具备对肿瘤相关巨噬细胞进行重编程的能力, 可促进CCL5和CXCL9的分泌, 进而将CD8⁺ T细胞招募至肿瘤部位, 与PD-1单克隆抗体(mAb) 治疗具有协同增效作用。Ou等^[47]研究发现, 从长春花叶片中分离得到的长春花叶囊泡(Catharanthus roseus leaf-derived exosome-like nanovesicles, CLDENs), 促进细胞因子TNF-α和IL-2分泌, 借助TNF-α/NF-κB/PU.1轴达成免疫反应的显著强化。Liu等^[48]从黄花蒿中分离纯化得到青蒿囊泡(Artemisia-derived nanovesicles, ADNVs), 发现植物来源的线粒体DNA (mitochondrial DNA, mtDNA) 通过囊泡内化到TAMs中, 作为诱导cGAS-STING通路的主要效应分子, 驱动促肿瘤巨噬细胞向抗肿瘤表型的转变。Xu等^[49]对大蒜囊泡在癌症免疫治疗中的作用进行了研究, 发现大蒜囊泡(garlic-derived nanoparticles, GNPs) 能够显著诱导肠道中产生干扰素γ (IFN-γ) 的γδ T细胞, 从而增强免疫检查点阻断疗法对实体瘤的疗效。这些γδ T细胞和IFN-γ从肠道转移到肠外皮下肿瘤, 重塑肿瘤免疫微环境, 协同抗PD-L1治疗, 诱导强大的抗肿瘤免疫反应。Ma等^[50]一种从连翘中提取得到的连翘囊泡(Hypericum perforatum-derived exosome-like nanovesicles, HPDENs), 可将其作为新型天然光敏剂应用于肿瘤光动力治疗(photodynamic therapy, PDT)。HPDENs在光照激活后能够通过I型和II型途径产生ROS, 对人黑色素瘤细胞表现出光剂量依赖性的细胞毒性, 增加ROS产生并诱导细胞凋亡; 同时, HPDENs介导的PDT显著抑制了肿瘤生长, 并诱导广泛的肿瘤坏死, 且未对主要器官造成可观察到的毒性。

3.3　调节免疫相关信号通路

调控免疫相关信号通路, 在维持免疫平衡与细胞功能、增强抗感染和抗肿瘤能力、影响肿瘤微环境, 以及提供临床应用前景等方面具有重要意义, 中草药囊泡通过调节免疫相关信号通路在抗肿瘤和炎症调节等方面展现出显著的潜力。中草药鸦胆子衍生的纳米囊泡(BF-Exos), 可作为一种高效的活性miRNA递送纳米平台, 通过PI3K/Akt/mTOR信号通路发挥抑制乳腺癌生长、转移和血管生成的疗效^[51]。野生甘草根部的纳米囊泡(Glycyrrhiza uralensis Fisch roots-derived nanovesicles, GC NV) 通过负载STING激动剂DMXAA和表面修饰PD-L1抗体, 达成对黑色素瘤的靶向治疗, 显著抑制肿瘤生长, 强化抗肿瘤免疫应答^[52]。Yang等^[53]研究发现, 新鲜人参囊泡可缓解炎症性肠病, 显著激活自噬和M2样巨噬细胞极化, 分泌更多的白介素-10 (IL-10), 并在体外显著降低肠上皮细胞中的一氧化氮水平, 通过IKK/IκB/NF-κB信号通路直接作用于肠上皮细胞, 以减轻肠道炎症。

综上所述, 中草药囊泡在肿瘤免疫治疗中展现出多方面的潜力, 调控免疫细胞功能、细胞因子分泌及免疫相关通路, 显著增强了机体的抗肿瘤免疫应答, 为肿瘤治疗提供了新的策略和方向(表1)^{[44, 45, 47-49, 51-55]}。

4　中草药囊泡通过调节代谢增效免疫

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鉴于中草药囊泡兼具代谢调控与免疫调节的双重活性, 其通过“代谢-免疫”双效协同机制重塑肿瘤微环境, 为癌症治疗提供了全新策略。作为这一双效调控过程的核心载体, 中草药囊泡通过靶向代谢重编程(如抑制糖酵解、调控脂质代谢) 间接激活抗肿瘤免疫应答, 同时直接调控免疫细胞功能(如巨噬细胞极化、T细胞活化), 从而协同增强整体抗肿瘤疗效。这种“代谢调控-免疫增效”的闭环机制, 凸显了中药囊泡在肿瘤联合治疗中的独特优势与临床转化潜力。

4.1　调控肿瘤细胞代谢增效免疫

中草药囊泡可以通过调控肿瘤微环境中肿瘤细胞的代谢过程, 直接抑制肿瘤细胞生长和增殖, 显著提升机体对肿瘤的免疫应答效能, 进而在抗肿瘤进程中发挥调控代谢增效免疫的双重效应。Huang等^[54]研究发现积雪草囊泡可以直接阻断肿瘤细胞关键代谢通路(如精氨酸/脯氨酸代谢、磷脂合成、嘌呤代谢), 切断能量与生物合成原料供应; 同时诱导ROS爆发和线粒体损伤, 触发凋亡。通过ROS介导的免疫原性细胞死亡(immunogenic cell death, ICD) 释放损伤相关分子模式, 激活树突状细胞抗原呈递; 并递送植物miRNA (如miR-396e) 靶向肿瘤糖酵解和免疫检查点, 重塑免疫微环境, 增强CD8⁺ T细胞和NK细胞杀伤功能, 通过“代谢抑制+ 免疫激活”双重机制发挥抗肿瘤作用。Yang等^[56]的研究发现人参囊泡通过抑制戊糖磷酸途径中的关键酶葡萄糖-6-磷酸脱氢酶和胸苷磷酸化酶, 阻断肿瘤细胞的能量和生物合成需求, 诱导氧化应激和凋亡, 间接免疫调控来抑制肺癌细胞的上皮-间充质转化和迁移能力, 改变肿瘤细胞的代谢状态, 重塑免疫微环境, 为免疫细胞的浸润和功能发挥创造了更有利的条件。Gao等^[57]从桑树叶片提取天然桑树叶囊泡, 通过半乳糖-ASGPR靶向肝癌细胞, 触发线粒体ROS爆发、膜电位下降及caspase激活, 同时下调HK2/PKM2 (糖酵解) 和CS/IDH1 (三羧酸循环), 导致ATP耗竭。口服桑树叶囊泡可以重塑肠道菌群, 增加有益菌(如乳酸菌) 并减少致病菌, 其短链脂肪酸经GPCR信号促进肝脏巨噬细胞M2极化, 上调IL-10, 恢复Treg/Th17平衡, 抑制NF-κB炎症通路。这种代谢杀伤与免疫调控的协同作用, 使桑树叶囊泡成为兼具高效低毒与口服便捷优势的肝癌治疗候选方案。由此, 中草药囊泡作为靶向代谢重编程的关键物质, 兼具增效免疫的功能, 在抗肿瘤治疗方面具有良好的应用前景。

中草药囊泡多组分中的关键内源性活性物质已有多项研究证明了其通过调控代谢实现免疫激活增效的作用。相较于其他来源的细胞外囊泡, 中草药囊泡展现出独特优势, 其囊腔内包裹着同源植物所含的药效活性物质。针对溶解性不佳的中草药活性成分, 中草药囊泡可有效提高其生物利用度, 为中草药活性成分的高效递送提供新策略。早期研究揭示, 人参囊泡内蕴含丰富的代谢产物, 且具备介导细胞间信号转导的功能。其中, 人参皂苷Rg3和磷脂为膜材包载雷公藤红素(celastrol, CEL) 的脂质体(CR-Lip), 可激活细胞ICD并调控肿瘤细胞内脂质代谢, 从CD8⁺ T细胞数量与功能两方面, 重塑肿瘤免疫抑制微环境(immunosuppressive tumor microenvironment, ITME), 协同增效免疫检查点阻断剂治疗肥胖小鼠黑色素瘤^[58]。生姜、绿茶^[55]、芝麻叶囊泡^[59]中含有多种多酚类化合物, 这些多酚类化合物通过抑制关键信号通路(如STAT1、STAT3、PI3K/Akt、mTOR等) 来下调PD-L1的表达, 进而增强T细胞对肿瘤细胞的免疫杀伤能力^[60]。姜黄囊泡中的内源性活性物质姜黄素^[27]也可以调控代谢增效免疫, Guo等^[61]研究发现姜黄素可以通过抑制HIF-1α和LDH-A/lactic acid信号通路, 干扰肿瘤细胞的糖酵解, 降低PD-L1的表达, 增强抗肿瘤免疫反应。

越来越多的研究从细胞代谢角度出发, 通过抑制肿瘤细胞相关代谢进程, 成为增效免疫的辅助方式, 而中草药囊泡作为多组分多靶向活性物质, 其在调控肿瘤代谢与免疫增效协同抗肿瘤中, 都展示出良好治疗潜力, 有望成为未来研究的关键。

4.2　调控免疫细胞代谢增效免疫

近年来, 研究聚焦于中草药囊泡, 发现其能够借助代谢调控机制, 直接作用于肿瘤微环境中的免疫细胞, 调节其功能状态, 为免疫治疗方案的优化提供了全新的增效途径。Liu等^[62]的研究表明, 鱼腥草囊泡(Houttuynia cordata-derived extracellular vesicles, HC-EVs) 可通过调控巨噬细胞线粒体代谢(如抑制线粒体膜电位下降、减少ROS产生), 间接影响肿瘤微环境代谢稳态。HC-EVs处理的巨噬细胞通过分泌代谢物(如乳酸、酮体), 可抑制肿瘤细胞Warburg效应(有氧糖酵解), 从而抑制肝癌细胞增殖。Lv等^[63]研究发现人参囊泡可以通过调节ARG1表达来影响TME中M1型巨噬细胞的精氨酸水平, 促进T细胞增殖与激活, 改善T细胞耗竭。体内外实验均证实了人参囊泡的抗肿瘤效果及其依赖mTOR-T-bet轴的机制, 导致ICs表达减少和CD8⁺ T细胞增强, 对人参健脾益气的功效作出新的科学解释, 丰富“扶正培本”的科学内涵。

这些研究不仅揭示了中草药囊泡及其功效物质在癌症治疗中的潜在应用价值, 还为开发新型联合治疗策略提供了科学依据。未来的研究将进一步探索中草药囊泡在不同癌症类型中的应用潜力, 通过中草药囊泡中的功能活性物质干预肿瘤微环境中免疫细胞的代谢, 实现代谢调控增效免疫的治疗作用。

5　总结与展望

收起

能量代谢治疗通过直接针对癌细胞或肿瘤微环境的代谢特点, 从源头上切断肿瘤细胞的能量和物质供应, 抑制肿瘤的生长和扩散, 对肿瘤的控制更为直接和迅速。癌细胞的代谢活动会塑造一个缺氧、酸性、营养匮乏的肿瘤微环境, 这种环境不仅有利于癌细胞的生存, 还会抑制免疫细胞的功能, 而能量代谢治疗可以逆转免疫抑制的肿瘤微环境, 使其更有利于免疫细胞的浸润和作用的发挥, 实现更强效的抗肿瘤治疗效果。

中草药乃传统医学核心构成, 于疾病防治举足轻重。近年来, 随着纳米技术和细胞外囊泡研究的不断深入, 中草药囊泡逐渐受到关注。从药用植物中提取的纳米级膜结构因其独特的来源与特性, 在医学领域展现出了巨大的应用潜力。中草药囊泡保留了母体植物的复杂活性成分, 形成“脂质-蛋白质-核酸-小分子”多组分协同体系。这种多靶点协同作用是单一化合物或动物源囊泡难以实现的。中草药囊泡的纳米级膜结构(10~300 nm) 赋予其天然组织亲和性, 可高效穿透生物屏障(如肠黏膜、血脑屏障)^[64]。

随着研究的不断深入, 人们发现中草药囊泡在疾病治疗和药物递送方面具有显著优势, 中草药囊泡通过“代谢重编程-免疫调控”双通路增效抗肿瘤, 发挥多组分的药理作用, 调控肿瘤微环境中各种细胞的代谢过程, 逆转免疫抑制的微环境, 为免疫系统提供更有力的支持, 实现调控代谢增效免疫的抗肿瘤治疗效果。这种“代谢-免疫”正反馈机制是中草药囊泡区别于传统药物的核心优势。

中草药囊泡凭借多组分协同、天然靶向性及代谢-免疫双靶点调控, 展现出独特的治疗潜力。未来需进一步标准化提取工艺、明确体内代谢机制, 并开展大规模临床转化研究, 以充分释放其在肿瘤、炎症等疾病治疗中的价值。在未来的研究中, 中草药囊泡有望成为疾病治疗的关键手段: ①在肿瘤治疗领域, 它们能够携带抗癌药物精准地攻击癌细胞, 同时对肿瘤微环境内的代谢失衡状态予以调节, 强化免疫细胞针对肿瘤的识别效能与杀伤效力, 为癌症患者提供全新的治疗方案; ②中草药囊泡不仅可以发挥治疗效应还可作为制剂载体, 稳定释放所加载药物, 以维持体内药物的有效浓度, 减轻患者的用药负担, 改善患者的全身状况, 提高生活质量; ③中草药囊泡还可以根据给药方式或患者的个体差异, 进行膜表面定制化修饰, 实现精准治疗, 为每一位患者量身打造最适合的治疗方案。然而, 中草药囊泡的研发和应用仍面临诸多挑战, 如何进一步提高中草药囊泡的稳定性和载药量, 如何深入理解其在体内的代谢机制和免疫调节作用, 如何实现大规模生产和质量控制等问题, 都需要科研人员持续探索和努力。中草药囊泡在通过调控代谢以增强免疫作用的未来探索中, 展现出巨大的应用潜力。它们有望为疾病治疗提供效率更高、安全性更优、个性化程度更强的治疗方案, 推动该研究领域迈向新的发展阶段, 为人类健康事业作出更为显著的贡献。

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2025年第60卷第9期

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doi: 10.16438/j.0513-4870.2025-0678

接收时间：2025-06-17
首发时间：2026-09-20
出版时间：2025-09-12

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收稿日期：2025-06-17
修回日期：2025-07-09

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¹南京中医药大学药学院, 江苏南京 210023

²江苏省中药高效给药系统工程技术研究中心, 江苏南京 210023

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王若宁, E-mail: ruoningw@njucm.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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Vesicle source	Application	Synergistic immune pathway	Ref.
Ginseng	Inhibit melanoma growth	Activated TLR4/MyD88 signaling pathway; polarized M1-like macrophages; altered the tumor immune microenvironment; elevated reactive oxygen species (ROS)	[44]
Platycodon grandiflorum	Regulate inflammation and repair lung damage	Increased the expression of anti-inflammatory factors; inhibited the release of inflammatory factors; controlled the glycolysis and lipid metabolism pathways of macrophages	[45]
Catharanthus roseus	Inhibit tumor growth	Promoting the secretion of cytokines TNF-α and IL-2; enhanced phagocytic function; promoted macrophage polarization and lymphocyte proliferation; enhanced the immune responses through the TNF-α/NF-κB/PU.1 axis	[47]
Artemisia annua	Inhibit lung cancer growth	Activated cGAS-STING pathway of macrophage by delivery of mitochondrial DNA (mtDNA) drives the transition of TAMs to an antitumor phenotype	[48]
Garlic	Enhance the efficacy of anti-PD-L1 immunotherapy	Activated intestinal γδ T cells to release IFN-γ; modified the tumor microenvironment; worked with PD-L1 inhibitors to improve immunity against tumors	[49]
Brucea javanica	Inhibit the growth of breast cancer	Inhibited the growth of breast cancer, metastasis and angiogenesis through the PI3K/Akt/mTOR signaling pathway	[51]
Glycyrrhiza uralensis Fisch roots	Inhibit the growth of melanoma	Inhibited tumor growth and enhanced the anti-tumor immune responses by loading the STING agonist DMXAA and surface-modifying with PD-L1 antibodies	[52]
Ginseng	Repair inflammatory bowel disease (IBD)	Activated autophagy; polarized M1-like macrophages; directly acts on intestinal epithelial cells through the IKK/IκB/NF-κB signaling pathway; restored the intestinal barrier	[53]
Aristolochia	Inhibit the proliferation of liver cancer cells	Regulated amino acid metabolism and glycerophospholipid metabolism in tumor cells; reduced lipid synthesis; induced ROS production and apoptosis; enhanced recognition of immune cells	[54]
Camellia sinensis	Inhibit breast cancer growth and metastasis	Promoted ROS production; killed tumor cells; regulated intestinal flora; enhanced systemic immune responses	[55]

Vesicle source

Application

Synergistic immune pathway

Ref.

Ginseng

Inhibit melanoma growth

Activated TLR4/MyD88 signaling pathway; polarized M1-like macrophages; altered the tumor immune microenvironment; elevated reactive oxygen species (ROS)

[44]

Platycodon grandiflorum

Regulate inflammation and repair lung damage

Increased the expression of anti-inflammatory factors; inhibited the release of inflammatory factors; controlled the glycolysis and lipid metabolism pathways of macrophages

[45]

Catharanthus roseus

Inhibit tumor growth

Promoting the secretion of cytokines TNF-α and IL-2; enhanced phagocytic function; promoted macrophage polarization and lymphocyte proliferation; enhanced the immune responses through the TNF-α/NF-κB/PU.1 axis

[47]

Artemisia annua

Inhibit lung cancer growth

Activated cGAS-STING pathway of macrophage by delivery of mitochondrial DNA (mtDNA) drives the transition of TAMs to an antitumor phenotype

[48]

Garlic

Enhance the efficacy of anti-PD-L1 immunotherapy

Activated intestinal γδ T cells to release IFN-γ; modified the tumor microenvironment; worked with PD-L1 inhibitors to improve immunity against tumors

[49]

Brucea javanica

Inhibit the growth of breast cancer

Inhibited the growth of breast cancer, metastasis and angiogenesis through the PI3K/Akt/mTOR signaling pathway

[51]

Glycyrrhiza uralensis Fisch roots

Inhibit the growth of melanoma

Inhibited tumor growth and enhanced the anti-tumor immune responses by loading the STING agonist DMXAA and surface-modifying with PD-L1 antibodies

[52]

Ginseng

Repair inflammatory bowel disease (IBD)

Activated autophagy; polarized M1-like macrophages; directly acts on intestinal epithelial cells through the IKK/IκB/NF-κB signaling pathway; restored the intestinal barrier

[53]

Aristolochia

Inhibit the proliferation of liver cancer cells

Regulated amino acid metabolism and glycerophospholipid metabolism in tumor cells; reduced lipid synthesis; induced ROS production and apoptosis; enhanced recognition of immune cells

[54]

Camellia sinensis

Inhibit breast cancer growth and metastasis

Promoted ROS production; killed tumor cells; regulated intestinal flora; enhanced systemic immune responses

[55]