天然药物自组装纳米粒的形成机制、构建及性能评价

Formation mechanisms, construction, and performance evaluation of self-assembled nanoparticles derived from natural products

摘要

自组装纳米粒(self-assembled nanoparticles，SANs)是一类通过分子间非共价相互作用自发形成的纳米尺度组装体。SANs可影响其活性成分的吸收及分布，且在生物活性方面优于游离活性成分或其简单混合物。通过纳米沉淀法、乳化-溶剂挥发法、溶剂热法等方法可构建天然药物SANs，其理化性质及药物释放等性能均优于原药物。然而，SANs的稳定性及工业化应用还有待进一步研究。基于SANs的优异性能，其有望成为下一代精准药物递送系统的重要载体，为重大疾病的治疗提供新策略。

Abstract

Self-assembled nanoparticles (SANs) are a class of nanoscale assemblies that spontaneously form through intermolecular non-covalent interactions. SANs can influence the absorption and distribution of their active components and often exhibit superior activity compared with free active compounds or their simple mixtures. Natural product-based SANs can be constructed using methods such as nanoprecipitation, emulsion-solvent evaporation, and solvothermal techniques, and their physicochemical properties and drug release performance are generally superior to those of the parent compounds. However, the stability and large-scale industrial application of SANs still require further investigation. Owing to their advantageous properties, SANs are expected to become important carriers in next-generation precision drug delivery systems, providing new strategies for the treatment of major diseases.

Graphical abstract

关键词

天然药物 / 自组装纳米粒 / 形成机制 / 构建方法 / 性能评价 / 药物释放 / 精准药物递送系统

Key words

natural products / self-assembled nanoparticles / formation mechanism / construction methods / performance evaluation / drug release / precision drug delivery systems

自组装纳米粒(self-assembled nanoparticles，SANs)是指通过分子间非共价作用自发形成的纳米粒，其可有效提高难溶性成分的生物利用度^[1]。天然药物指经验证具有药理活性的动物药、植物药、矿物药及微生物来源药物，其中以植物药最为常见，种类繁多^[2]。天然药物SANs是以天然活性成分为构建单元的SANs。SANs具有良好的生物利用度、降解性、相容性和易于功能修饰的特性^[3]，对揭示天然药物配伍机制、研发新药及开发新型纳米材料具有重要意义^[4]，在肿瘤的治疗方面亦展现出显著优势^[5-6]。以Web of Science核心合集作为数据来源，利用其自带的文献计量分析功能对相关文献进行统计。结果表明，SANs相关的研究呈逐年增长趋势，其中中国和美国的发文量最大。发表于北大核心期刊的文献共87篇；沈阳药科大学和天津大学是发表相关论文最多的研究机构。当前热点集中于自组装机制、靶向递送与肿瘤治疗等方面，并呈现出向工程化制备、智能设计与临床转化发展的清晰趋势。本文将综述天然药物SANs的结构、形成机制、构建方法及性能评价方法，旨在为相关药物制剂及药物递送系统的研究提供参考。

1 SANs概述

1.1 SANs的结构

SANs的结构类型多样，目前常见的包括核壳结构、胶束结构和脂质体结构等。

1.1.1 核壳结构

普通的药物载体可能会使负载药物在非目标生理环境中过早释放，为解决此类问题，Terrón-Mejía 等^[7]使用带相反电荷的壳聚糖与磷脂通过静电作用自组装成具有核壳结构的SANs。其中，磷脂形成的内核有效包封疏水性辣椒素，其疏水环境能延缓药物扩散。同时，壳聚糖在外围形成亲水外壳，不仅增强稳定性，其表面性质也为实现靶向递送与释放调控提供了可能。

核壳结构的SANs因核壳材料的不同组合，可呈现出多种功能，如延长被封装药物释放时间、减少暴发释放、实现被封装物质多阶段释放等^[8]。

1.1.2 胶束结构

胶束结构的SANs包含1个疏水核心，可搭载不同种类的不溶性药物；同时具有1个亲水外壳，可防止药物与单核吞噬系统相互作用。当目标药物被封装在聚合物胶束(polymeric micelles，PM)纳米载体中时，被包封药物的溶解性和治疗指数均有所提高^[9-10]。胶束结构凭借其独特的亲疏水微环境，显著提升了难溶性天然药物的生物利用度与治疗效能，是极具潜力的纳米递送体系。

1.1.3 脂质体结构

脂质体是由磷脂、胆固醇等脂质分子自组装形成的纳米级球形囊泡结构，药物被包封于脂质体中后，其溶解性、生物分布、药代动力学及治疗指数均得到显著改善，同时可降低药物的毒副作用^[11]。研究^[12]表明，脂质体作为药物递送载体，在肿瘤治疗、疫苗递送、核酸药物递送等领域展现出优异的生物相容性与治疗效果，是当前最具临床应用前景的纳米递送系统之一。

1.2 SANs的形成机制

目前研究较多的SANs形成机制主要包括静电相互作用、疏水相互作用及π-π堆积效应等，这些作用的本质均为分子间作用力^[13-14]。药物自组装过程通常由2种或多种非共价键的协同作用驱动(图1)。

1.2.1 静电相互作用

带净电荷的NPs之间存在库仑作用。当其所带净电荷少至3个时，可以在水中有效地诱导带相反电荷的NPs相互结合，形成更高级的结构。瞬时纳米粒组装体则可以由带正电的NPs和带负电的多电荷阴离子生成^[15-16]。静电相互作用为构建结构多样的纳米组装体提供了普适而高效的驱动力，尤其在多糖等天然大分子体系中应用广泛。

1.2.2 疏水相互作用

具有核壳结构的PM是目前研究最广泛的疏水递送纳米载体之一。由于成核段之间的疏水相互作用，PM的疏水核心常用作疏水药物的纳米容器，而亲水聚合物(如聚乙二醇)则作为外壳用于增强胶体稳定性^[17]。疏水作用也是高阶核酸自组装纳米结构的构建机制之一^[18]。

1.2.3 π-π堆积

小分子的π-π堆积在电荷传输过程中发挥着重要作用。共轭小分子的π-π堆积在不同程度上受到其他分子的影响，利用这一特性，可通过精确的化学修饰调控π-π堆积程度，从而改变电荷传输特性^[19]。在光催化领域中，卟啉分子SANs的π-π堆积应用尤为典型^[20]。该机制不仅能提供稳定的组装驱动力，还能赋予纳米粒独特的光电性质，拓展了其在光动力治疗等前沿领域的应用范围。

1.2.4 多机制协同自组装

在实际体系中，天然药物自组装往往并非由单一作用力独立驱动，而是多种非共价协同作用的结果。不同作用力在自组装的不同阶段和空间结构中发挥主次不同的作用。

一般而言，静电相互作用常在自组装初期主导分子识别与快速聚集，疏水作用为纳米粒核心结构的稳定形成提供主要驱动力，而π-π堆积则主要参与调控分子排列方式及纳米结构的致密性与功能特性。在同一自组装体系中，这些作用力相互耦合、相互增强，共同决定纳米粒的最终形貌、稳定性及生物学性能^[21]。

2 天然药物SANs的制备方法

天然药物SANs的制备方法较多，主要包括纳米沉淀法、乳化-溶剂挥发法、溶剂热法、薄膜水合法等^[22-25]。此外，壳聚糖-天然药物SANs是近年的研究热点，其主要制备方法为离子交联法^[26]。天然药物SANs主要制备方法的工艺、参数和递送药物见表1。

2.1 离子交联法

离子交联法是制备壳聚糖纳米粒的一种常用方法，具有生物安全性高、操作简单和反应条件温和等优点^[27]。通过此法，槲皮素(quercetin，Que)通过疏水作用自发嵌入壳聚糖与三聚磷酸钠(sodium tripolyphosphate，TPP)经静电作用交联而成的纳米网格中，形成Que-壳聚糖/TPP SANs，可显著提升药物的缓释性与抗癌活性^[20]；小檗碱-壳聚糖/TPP SANs亦可借助此法制备^[28]。离子交联法条件温和、生物相容性好，能很好地保护药物活性，且其形成的网格结构可构建较高包封率的纳米粒。

2.2 纳米沉淀法

纳米沉淀法因其操作简便且绿色环保等特性，成为制备无载体纳米药物的常用方法。将Que与FeCl₃、卵磷脂溶于乙醇后滴入水中，再加入葛根素(puerarin，Pue)进行共沉淀，制得Que/Fe/Pue纳米粒。该策略显著改善了Que和Pue的水溶性，并赋予纳米粒抗氧化、线粒体靶向和促血管生成等功能^[35]。Tian等^[36]在超声条件下将雷公藤红素和毛兰素的二甲基亚砜溶液滴入水相中自组装形成雷公藤红素-毛兰素SANs，有效改善了两者的溶解性与毒性。Gao等^[37]采用纳米沉淀法制备了小檗碱和橙皮素SANs，其疗效显著优于单独用药。

纳米沉淀法虽操作简便，但也存在一些局限：其制得的SANs的形貌和尺寸分布易受药物浓度、温度及溶剂类型等参数影响^[38-39]，难以满足工业化大规模生产的需求。

2.3 乳化-溶剂挥发法

乳化-溶剂挥发法是一种通过引入有机溶剂构建乳液，制备活性物质递送载体的方法^[45-46]。胡迪迪等^[47]为改善青蒿素(artemisinin，ART)的水溶性及优化聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic) acid，PLGA]纳米粒的制备工艺，将ART和PLGA溶于二氯甲烷，滴入含聚乙烯醇的水相中进行超声乳化，随后搅拌挥发有机溶剂并经离心洗涤，制得PLGA-ART-NPs纳米递送系统。该法也成功制备了7-羟乙基白杨素(7-hydroxyethyl chrysin，7-HEC)纳米粒，解决了7-HEC口服吸收差的问题^[48]。该方法已被证明是包载疏水性天然药物的有效策略，但后续工艺中彻底去除有机溶剂并保证载药纳米粒的稳定性是其质量控制的关键。

2.4 溶剂热法

溶剂热法的优势在于非水溶剂规避了水热法对天然药物活性成分的水解风险，同时高压环境精准调控了纳米粒形貌，为靶向递送提供理想载体^[54]。大黄酸-和厚朴酚SANs的制备即采用此法^[55]。溶剂热法在苛刻条件下仍能较好地保持天然药物的活性，并能精细调控纳米结构，为高性能纳米药物的制备提供了新思路。

2.5 薄膜水合法

薄膜水合法也可用于制备天然药物SANs，其纳米粒形态主要为胶束或囊泡^[61]。为提高姜黄素(curcumin，Cur)生物利用度，将牛膝提取的超分子自组装体(achyranthes bidentata supramolecular self-assemblies，NXSSA)与Cur溶于乙醇后，采用该法制备得到有良好缓释特性和免疫调节功能的牛膝-姜黄素(achyranthes bidentata-curcumin，NX@Cur)纳米粒^[62]。此外，将姜黄素与甘草次酸-聚乙烯亚胺-聚乳酸-羟基乙酸[glycyrrhetinic acid-polyethyleneimine-poly(lactic-co-glycolic acid)，GA-PEI-PLGA]共聚物溶于甲醇/二氯甲烷混合溶剂，采用此法亦可获得姜黄素SANs^[63]。尽管该方法重现性好，适用于制备脂质体或聚合物胶束，但过程较为繁琐，且对操作条件有一定要求。

3 天然药物SANs的性能

3.1 物理表征

SANs的物理表征主要聚焦于形貌特征、粒径分布、内部结构及稳定性等，这些性质对其在体内的分布特性、药物递送效果及靶向性均有重要影响^[70]。

形貌特征方面，扫描电子显微镜(scanning electron microscope，SEM)和透射电子显微镜(transmission electron microscope，TEM)是最常用的技术手段^[71-73]。近年来，原子力显微镜也逐渐用于研究聚合物纳米纤维及复合材料的表面形态、机械性能、填料分散等情况，通过观察填料在基体中的分布和形态，评估其对材料性能的影响^[74-75]。纳米粒的稳定性是评价其性能的重要因素，常用粒径、Zeta电位等作为表征指标^{[23, 76-77]}，常用检测方法包括SEM、TEM和光谱技术(动态光散射)^[78]。近年来，质谱法因其在大尺寸范围内悬浮液中的粒径测量潜力，为纳米粒的粒度测量提供了新的替代方法^[79]。除上述静态观测技术以外，de Jonge等^[80]利用原位液相TEM技术实时追踪纳米粒的成核、生长与组装过程，为研究其形成动力学和稳定性提供了有力工具。场发射TEM作为一种先进的分析手段，也可用于观察SANs的形貌和尺寸^[81]。

3.2 化学成分表征

化学成分表征用于解析天然药物中活性成分与生物大分子的种类、含量及互作机制。孟雨婷等^[82]采用高效液相色谱(high performance liquid chromatography，HPLC)法测定了甘草SANs中6种活性成分的含量，并对三黄泻心汤中的SANs进行成分分析，鉴定出生物碱类等14种化合物。

此外，离子迁移谱-质谱联用通过增加离子尺寸分离维度，可有效区分共洗脱组分和同分异构体，为解析纳米粒复杂化学成分提供了高分辨率手段^[83]。随着分析技术的升级，对复杂天然药物纳米体系中多种成分的定性、定量分析能力也在不断提高，为阐明其组装机制与物质基础提供了有力支撑。

3.3 包封率及载药量

包封率是评价纳米药物载体的制备工艺和质量的重要指标^[84]。目前测定小分子物质常用HPLC法^[85-86]，对于蛋白质类药物(如血清白蛋白)则常采用荧光分光光度计进行测定。Bouchemal等^[87]采用等温滴定量热法(isothermal titration calorimetry，ITC)实时监测药物-载体结合的热力学过程，实现了包封率与载药量的无分离测定，并同步获得结合常数、计量比及热力学驱动力。与此同时，能实现高效分离、具有高灵敏度的液相色谱-串联质谱法(liquid chromatography-tandem mass spectrometry，LC-MS)亦可精准、快速、无干扰地完成包封率和载药量的测定^[39]。

3.4 药物体外溶出与释放

纳米药物的体外溶出与释放是关键质量属性，能反映其体内行为^[88]。纳米药物释放受多种因素影响，如粒径、载体、孔径、环境因素等。体外释放度测定常用透析法、离心法和流通池法。Yan等^[89]研究黄芩苷(baicalin，BA)和巴马汀(palmatine，PA)联合SANs的释放行为，通过透析-HPLC测得4 h内黄芩苷的溶出率，其中单药≈0%，而与巴马汀共组装的纳米粒>70%，表明自组装可显著促进黄芩苷的释放。近年来，随着仿生技术的发展，三维打印技术也开始被用于更精准地评估纳米药物的释放行为。Goyanes等^[90]利用三维打印技术构建了具有仿生结构和生理环境的胃肠道模型，该模型可模拟体内环境，优于传统溶出装置，为SANs的释放提供了更精准的体外评估平台。发展能更好地模拟体内复杂环境的体外释放评价方法，对于精准预测SANs的体内药效与行为具有重要意义，是连接实验室研究与临床应用的重要桥梁。

4 结语与展望

本文系统梳理了天然药物SANs的构建及性能评价研究进展。在构建方面，核壳结构、胶束结构和脂质体结构等多样化的SANs通过静电作用、疏水作用和π-π堆积等非共价相互作用形成，并表现出良好的载药能力和靶向性。常用制备方法包括纳米沉淀法、乳化-溶剂挥发法、溶剂热法等。性能评价则主要依托理化表征，以实现质量可控。

尽管天然药物SANs研究取得了显著进步，但仍存在以下不足。首先，现有的制备工艺虽在实验室条件下均可实现天然药物SANs的构建，但多依赖经验性参数调控，缺乏对纳米粒形成过程中分子聚集、结构重排等关键动力学过程的精确控制。受限于传质方式、设备精度及工艺连续化水平，这些工艺在放大制备时易产生粒径和结构差异，导致批次稳定性不足，同时增加能耗、成本及质量控制难度，限制其工业化应用。其次，纳米粒在复杂生理环境中稳定性不足，长期储存易发生聚集或药物泄漏。此外，纳米粒的体内分布、代谢途径及潜在毒性研究不足，缺乏系统药代动力学和安全性评价数据。现有纳米粒的靶向机制多依赖被动靶向，主动靶向和多重刺激响应系统的设计仍有待突破。

未来研究可从以下方向展开：1)探索微流控技术、三维打印等新型制备方法，提高纳米粒的均一性和生产效率。陈等^[91]通过三维打印成功制得基于纳米粒的伤口愈合填充剂，为相关研究提供了借鉴。2)通过表面修饰或新型交联策略增强纳米粒的稳定性和智能响应性。例如，Mousavi等^[92]使用三乙氧基硅烷对石墨烯纳米粒进行表面修饰，发现其稳定性显著提高。Pouso等^[93]以一种纳米胶体为基材，制备了基于双交联型泊洛沙姆407的水凝胶，其降解时间延长，且可在近红外光下产生局部光致热效应。3)结合计算机辅助设计和人工智能，解析纳米粒的体内代谢途径、药效机制及与生物系统的相互作用。例如，Shan等^[94]通过计算机辅助策略识别理化性质，指导设计自组装化合物，解析了羟氯喹-维生素E琥珀酸-硼替佐米纳米粒的体内靶向递送、溶酶体碱化及免疫调控过程；而人工智能利用机器学习建模分析纳米粒性质，预测其体内行为与疗效^[95]。4)探索SANs在联合治疗、基因递送和跨屏障递送中的应用潜力。通过多学科交叉创新，SANs有望成为下一代精准药物递送系统的重要载体，为重大疾病的治疗提供新策略。

参考文献

[1] 袁海龙, 朱煜文. 中药制剂研究新方向: 改良自组装纳米粒的构建及应用[J]. 中国中药杂志, 2025, 50(13): 3569-3573.

[2] YUAN Hailong, ZHU Yuwen. A new research direction of traditional Chinese medicine preparations: development and application of improved self-assembled nanoparticles[J]. China Journal of Chinese Materia Medica, 2025, 50(13): 3569-3573.

[3] 刘荣华. 天然药物化学专论[M]. 北京: 科学出版社, 2024: 1-2.

[4] LIU Ronghua. Monography of medicinal chemistry of natural products[M]. Beijing: Science Press, 2024: 1-2.

[5] Cui W, Li J, Decher G. Self-assembled smart nanocarriers for targeted drug delivery[J]. Adv Mater, 2016, 28(6): 1302-1311.

[6] Li T, Wang P, Guo W, et al. Natural berberine-based Chinese herb medicine assembled nanostructures with modified antibacterial application[J]. ACS Nano, 2019, 13(6): 6770-6781.

[7] Li D, Zhang R, Liu G, et al. Redox-responsive self-assembled nanoparticles for cancer therapy[J]. Adv Healthc Mater, 2020, 9(20): 2000605.

[8] 李婷婷. 自组装靶向纳米系统共递送姜黄素与阿霉素治疗肺癌的研究[D]. 成都: 四川大学, 2023.

[9] LI Tingting. Co-delivery of curcumin with doxorubicin via self-assembled targeted nano-delivery system for treatment of lung cancer[D]. Chengdu: Sichuan University, 2023.

[10] Terrón-Mejía KA, Martínez-Benavidez E, Higuera-Ciapara I, et al. Mesoscopic modeling of the encapsulation of capsaicin by lecithin/chitosan liposomal nanoparticles[J]. Nanomaterials, 2018, 8(6): 425.

[11] Qiu J, Li X, Steenkeste K, et al. Self-assembled multifunctional core-shell highly porous metal-organic framework nanoparticles[J]. Int J Pharm, 2020, 581: 119281.

[12] Khan S, Vahdani Y, Hussain A, et al. Polymeric micelles functionalized with cell penetrating peptides as potential pH-sensitive platforms in drug delivery for cancer therapy: a review[J]. Arab J Chem, 2021, 14(8): 103264.

[13] Sinha S, Tripathi AK, Pandey A, et al. Self-assembled PEGylated micelles for precise and targeted drug delivery: Current challenges and future directions[J]. Biocatal Agric Biotechnol, 2024, 60: 103296.

[14] 任琎, 李计来, 李树香. 脂质体作为药物递送载体的研究进展[J]. 国际生物制品学杂志, 2025, 48(3): 198-205.

[15] REN Jin, LI Jilai, LI Shuxiang. Research progress of liposomes as drug delivery carriers[J]. International Journal of Biologicals, 2025, 48(3): 198-205.

[16] Wang Q, Wei N, Guo J, et al. Hemin-lipid assembly as an artemisinin oral delivery system for enhanced cancer chemotherapy and immunotherapy[J]. Nanoscale, 2021, 13(31): 13231-13240.

[17] 冯星星, 谢琪, 杨丛莲, 等. 基于中药活性成分自组装的无载体纳米制剂[J]. 药学学报, 2021, 56(12): 3203-3211.

[18] FENG Xingxing, XIE Qi, YANG Conglian, et al. Carrier-free nanoparticles based on self-assembly of active ingredients from Chinese medicine[J]. Acta Pharmaceutica Sinica, 2021, 56(12): 3203-3211.

[19] Wang C, Fu L, Hu Z, et al. A mini-review on peptide-based self-assemblies and their biological applications[J]. Nanotechnology, 2021, 33(6): 062004.

[20] Bian T, Gardin A, Gemen J, et al. Electrostatic co-assembly of nanoparticles with oppositely charged small molecules into static and dynamic superstructures[J]. Nat Chem, 2021, 13(10): 940-949.

[21] Mendes AC, Strohmenger T, Goycoolea F, et al. Electrostatic self-assembly of polysaccharides into nanofibers[J]. Colloids Surf A Physicochem Eng Aspects, 2017, 531: 182-188.

[22] Zhang J, Ellsworth K, Ma PX. Hydrophobic pharmaceuticals mediated self-assembly of beta-cyclodextrin containing hydrophilic copolymers: novel chemical responsive nano-vehicles for drug delivery[J]. J Control Release, 2010, 145(2): 116-123.

[23] Xiao F, Chen Z, Wei Z, et al. Hydrophobic interaction: a promising driving force for the biomedical applications of nucleic acids[J]. Adv Sci, 2020, 7(16): 2001048.

[24] Liu Y, Xu Z, Zhang J, et al. Tuning morphology and functionality of two-component self-assembly induced by H-bond and π-π stacking[J]. Dyes and Pigments, 2019, 170: 107586.

[25] 吴丽冉, 王营超, 刘姗姗, 等. 木质素纳米颗粒的可控制备及应用进展[J]. 中国造纸, 2021, 40(4): 73-84.

[26] WU Liran, WANG Yingchao, LIU Shanshan, et al. Controllable preparation of lignin nanoparticle and its application[J]. China Pulp & Paper, 2021, 40(4): 73-84.

[27] Hu Y, Peng J, Liu R, et al. Porphyrin-based supramolecular self-assemblies: construction, charge separation and transfer, stability, and application in photocatalysis[J]. Molecules, 2024, 29(24): 6063.

[28] Huang L, Zhao S, Fang F, et al. Advances and perspectives in carrier-free nanodrugs for cancer chemo-monotherapy and combination therapy[J]. Biomaterials, 2021, 268: 120557.

[29] Wang J, Zhao H, Zhi K, et al. Exploration of the natural active small-molecule drug-loading process and highly efficient synergistic antitumor efficacy[J]. ACS Appl Mater Interfaces, 2020, 12(6): 6827-6839.

[30] Ji H, Wang W, Li X, et al. Natural small molecules enabled efficient immunotherapy through supramolecular self-assembly in P53-mutated colorectal cancer[J]. ACS Appl Mater Interfaces, 2022, 14(2): 2464-2477.

[31] Thabet Y, Elsabahy M, Eissa NG. Methods for preparation of niosomes: a focus on thin-film hydration method[J]. Methods, 2022, 199: 9-15.

[32] Park JK, Chung MJ, Choi HN, et al. Effects of the molecular weight and the degree of deacetylation of chitosan oligosaccharides on antitumor activity[J]. Int J Mol Sci, 2011, 12(1): 266-277.

[33] Wang Y, Zhao B, Wang S, et al. Formulation and evaluation of novel glycyrrhizic acid micelles for transdermal delivery of podophyllotoxin[J]. Drug Deliv, 2016, 23(5): 1623-1635.

[34] Wang H, Deng H, Gao M, et al. Self-assembled nanogels based on ionic gelation of natural polysaccharides for drug delivery[J]. Front Bioeng Biotechnol, 2021, 9: 703559.

[35] 吴晓莹, 胡媛, 曹建平. 细粒棘球绦虫多肽-壳聚糖季铵盐纳米颗粒的制备[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(3): 300-305, 311.

[36] WU Xiaoying, HU Yuan, CAO Jianping. Preparation of Echinococcus granulosus peptide embedded in chitosan quaternary ammonium salt nanoparticles[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2023, 41(3): 300-305, 311.

[37] 李翔, 张鹏, 刘亚丽, 等. 治疗白内障的姜黄素N-三甲基壳聚糖纳米粒的制备及其初步药效学研究[J]. 中国医药工业杂志, 2017, 48(12): 1766-1771.

[38] LI Xiang, ZHANG Peng, LIU Yali, et al. Preparation and preliminary efficacy of curcumin-loaded N-trimethyl chitosan nanoparticles for cataract treatment[J]. Chinese Journal of Pharmaceuticals, 2017, 48(12): 1766-1771.

[39] 何黎黎, 邓黎, 林芸竹. 红景天苷壳聚糖纳米粒的制备及其体外释放性能研究[J]. 中草药, 2013, 44(5): 552-556.

[40] HE Lili, DENG Li, LIN Yunzhu. Preparation and in vitro drug release properties of salidroside-chitosan nanoparticles[J]. Chinese Traditional and Herbal Drugs, 2013, 44(5): 552-556.

[41] 邢志华, 方桂珍, 苏玲, 等. 羟基喜树碱叶酸-壳聚糖纳米粒的制备及其性能研究[J]. 功能材料, 2012, 43(S2): 322-325.

[42] XING Zhihua, FANG Guizhen, SU Ling, et al. Preparation and characterization of hydroxycamptothecin loated folate-chitosan nanoparticles as a sustained-release drugs carrier[J]. Journal of Functional Materials, 2012, 43(S2): 322-325.

[43] 吴思晓, 周玥莹, 于慧敏, 等. 反式白藜芦醇纳米粒的制备及其体外评价[J]. 华侨大学学报(自然科学版), 2019, 40(6): 771-778.

[44] WU Sixiao, ZHOU Yueying, YU Huimin, et al. Preparation and in vitro evaluation of trans-resveratrol nanoparticles[J]. Journal of Huaqiao University. Natural Science, 2019, 40(6): 771-778.

[45] 吕凤娇, 刘娟, 袁昕, 等. 离子诱导结合化学交联法制备黄芩苷壳聚糖纳米粒[J]. 泉州师范学院学报, 2020, 38(2): 1-8.

[46] Fengjiao LÜ, LIU Juan, YUAN Xin, et al. The preparation of baicalin-chitosan-nanoparticles by ion-induced combining chemical crosslinking[J]. Journal of Quanzhou Normal University, 2020, 38(2): 1-8.

[47] Chen Y, Ren T, Wu W, et al. Gas-propelled anti-hair follicle aging microneedle patch for the treatment of androgenetic alopecia[J]. J Control Release, 2025, 379: 636-651.

[48] Tian J, Chen K, Zhang Q, et al. Mechanism of Self-Assembled Celastrol-Erianin Nanomedicine for treatment of breast cancer[J]. Chem Eng J, 2024, 499: 155709.

[49] Gao S, Zheng H, Xu S, et al. Novel natural carrier-free self-assembled nanoparticles for treatment of ulcerative colitis by balancing immune microenvironment and intestinal barrier[J/OL]. Adv Healthc Mater, 2023, 12(31): e2301826[2025-10-01].

[50] Mori J, Miyashita Y, Oliveira D, et al. Stopped-flow analysis on the mechanism of perylene nanoparticle formation by the reprecipitation method[J]. J Cryst Growth, 2009, 311(3): 553-555.

[51] Xu L, Wang X, Liu Y, et al. Lipid nanoparticles for drug delivery[J]. Adv NanoBiomed Res, 2022, 2(2): 2100109.

[52] 庄子钰, 张帅, 王渤达, 等. 穗花杉双黄酮PLGA纳米粒的制备、表征及其体外抗肿瘤活性[J]. 山西医科大学学报, 2024, 55(11): 1437-1442.

[53] ZHUANG Ziyu, ZHANG Shuai, WANG Boda, et al. Preparation, characterization, and in vitro antitumor activity of amentoflavone-PLGA nanoparticles[J]. Journal of Shanxi Medical University, 2024, 55(11): 1437-1442.

[54] 史艳萍, 李学敏, 陈宝泉, 等. 生物素化普鲁兰多糖纳米颗粒制备与表征[J]. 功能材料, 2009, 40(1): 112-115.

[55] SHI Yanping, LI Xuemin, CHEN Baoquan, et al. Preparation and characteristics of biotinylated pullulan nanoparticles[J]. Journal of Functional Materials, 2009, 40(1): 112-115.

[56] 中国药科大学. 一种金色酰胺醇酯-半枝莲碱-棕榈酸酯自组装纳米粒及其制备方法和应用: CN202110568383.2[P]. 2022-03-08.

[57] China Pharmaceutical University. A gold acetamide alcohol ester-homocine-palmitate self-assembled nanoparticles and its preparation and application: CN202110568383.2[P]. 2022-03-08.

[58] 南开大学. 一种具有协同解热镇痛抗炎效果的药物组合物及应用: CN202411759181.6[P]. 2025-03-07.

[59] Nankai University. A pharmaceutical composition with synergistic antipyretic, analgesic, and anti-inflammatory effects and its application: CN202411759181.6[P]. 2025-03-07.

[60] 华中农业大学. 一种自组装纳米粒及其制备方法和应用: CN202310589684.2[P]. 2023-08-18.

[61] Huazhong Agricultural University. A self-assembled nanoparticle and its preparation method and application: CN202310589684.2[P]. 2023-08-18.

[62] 韦雅杰, 高彦祥. 乳化溶剂蒸发法在递送体系中的应用[J]. 中国食品学报, 2024, 24(3): 356-369.

[63] WEI Yajie, GAO Yanxiang. The application of emulsification solvent evaporation method in delivery system[J]. Journal of Chinese Institute of Food Science and Technology, 2024, 24(3): 356-369.

[64] 许俊, 钱文斌. 乳化–溶剂挥发法制备5-氟尿嘧啶聚乳酸微球及其缓释过程的研究[J]. 化学工程与技术, 2022, 12(6): 365-374.

[65] XU Jun, QIAN Wenbin. Preparation of 5-fluorouracil polylactic acid microspheres by emulsification-solvent volatilization method and its sustained release process[J]. Hans Journal of Chemical Engineering and Technology, 2022, 12(6): 365-374.

[66] 胡迪迪, 薛昊, 金旭东, 等. 单因素结合Box-Benhnken响应曲面法优化载青蒿素聚乳酸-羟基乙酸共聚物纳米粒制备工艺[J]. 天然产物研究与开发, 2024, 36(9): 1592-1599, 1572.

[67] HU Didi, XUE Hao, JIN Xudong, et al. Optimization of the preparation technics of artemisinin-loaded lactic-co-glycolic acid nanoparticles based on Box-Benhnken response surface method combined with a single factor analysis[J]. Natural Product Research and Development, 2024, 36(9): 1592-1599, 1572.

[68] 王小娟, 杨宝乐, 马川, 等. 7-羟乙基白杨素聚乳酸-羟基乙酸共聚物纳米粒的制备及体外释放评价[J]. 浙江大学学报(医学版), 2024, 53(1): 116-125.

[69] WANG Xiaojuan, YANG Baole, MA Chuan, et al. Preparation of copolymer 7-hydroxyethyl chrysin loaded PLGA nanoparticles and the in vitro release[J]. Journal of Zhejiang University. Medical Sciences, 2024, 53(1): 116-125.

[70] 李晴宇, 叶晓莉, 陈玲, 等. 姜黄素PLGA纳米粒的制备及制剂学性质分析[J]. 实用药物与临床, 2016, 19(6): 753-757.

[71] LI Qingyu, YE Xiaoli, CHEN Ling, et al. Preparation of curcumin-loaded poly(lactic-co-glycolic acid) nanoparticles and analysis of its nature[J]. Practical Pharmacy and Clinical Remedies, 2016, 19(6): 753-757.

[72] 叶琳, 徐凤男, 何流, 等. 基于三苯基膦修饰的线粒体靶向7-羟基香豆素纳米粒的制备及其性质[J]. 湖北科技学院学报(医学版), 2021, 35(5): 382-387, 364.

[73] YE Lin, XU Fengnan, He Liu, et al. Preparation and properties of 7-hydroxycoumarin nanoparticles based on triphenylphosphine mitochondria[J]. Journal of Hubei University of Science and Technology. Medical Sciences, 2021, 35(5): 382-387, 364.

[74] 浙江工业大学. 酶敏感性两亲性聚酯MePEGPeptidePERCL给药纳米粒的制备方法与流程: CN201710694241.4[P]. 2020-04-07.

[75] Zhejiang University of Technology. Preparation method of enzyme-sensitive amphiphilic polyester MePEG-Peptide-PER-CL drug-loaded nanoparticles: CN201710694241.4[P]. 2020-04-07.

[76] 黄华婷, 吴念, 蔡梦如, 等. 共载姜黄素和IR780的聚乳酸-羟基乙酸共聚物纳米粒的制备及其体外抗肿瘤评价[J]. 中草药, 2023, 54(2): 498-508.

[77] HUANG Huating, WU Nian, CAI Mengru, et al. Preparation and in vitro antitumor evaluation of PLGA nanoparticles co-loaded with curcumin and IR780[J]. Chinese Traditional and Herbal Drugs, 2023, 54(2): 498-508.

[78] 潘艺茗, 黄岳山. 聚乳酸/聚乙二醇琥珀酸酯-姜黄素纳米粒的制备及体外评价[J]. 中国组织工程研究, 2012, 16(3): 421-425.

[79] PAN Yiming, HUANG Yueshan. Preparation and in vitro evaluation of poly(lactide)/tocopheryl polyethylene glycol succinate-curcumin nanoparticles[J]. Chinese Journal of Tissue Engineering Research, 2012, 16(3): 421-425.

[80] Hussain MK, Liu R, Tanveer M, et al. Hydrogen and organic synthesis from wastewater with nano photocatalysts: a synergy[J]. Chemical Synthesis, 2025, 5(3): 40.

[81] 华中农业大学. 基于天然活性成分复方自组装纳米凝胶剂及其制备方法与应用: CN202310585056.7[P]. 2023-07-25.

[82] Huazhong Agricultural University. Compound self-assembled nanogel based on natural active ingredients and its preparation method and application: CN202310585056.7[P]. 2023-07-25.

[83] Kitture R, Ghosh S, Kulkarni P, et al. Fe₃O₄-citrate-curcumin: Promising conjugates for superoxide scavenging, tumor suppression and cancer hyperthermia[J]. J Appl Phys, 2012, 111(6): 064702.

[84] Qi M, Zhang K, Li SQ, et al. Superparamagnetic Fe₃O₄ nanoparticles: synthesis by a solvothermal process and functionalization for a magnetic targeted curcumin delivery system[J]. New J Chem, 2016, 40(5): 4480-4491.

[85] Miri NY, Eikani MH, Khandan N, et al. Preparation of nano-curcumin by subcritical water: Assessment of stability, dissolution rate and antioxidant activity[J]. J Mol Liq, 2024, 413: 126019.

[86] Hettiarachchi SS, Dunuweera SP, Dunuweera AN, et al. Synthesis of curcumin nanoparticles from raw turmeric rhizome[J]. ACS Omega, 2021, 6(12): 8246-8252.

[87] Bourang S, Asadian S, Noruzpour M, et al. PLA-HA/Fe₃O₄ magnetic nanoparticles loaded with curcumin: physicochemical characterization and toxicity evaluation in HCT116 colorectal cancer cells[J]. Discov Appl Sci, 2024, 6(4): 186.

[88] Song Y, Zhang N, Li Q, et al. Biomimetic liposomes hybrid with platelet membranes for targeted therapy of atherosclerosis[J]. Chem Eng J, 2021, 408: 127296.

[89] Zhao M, Xiang J, Meng Y, et al. Astragalus polysaccharide hydrogels with drug-carrying super self-assembly from natural herbs promote wound healing[J]. ACS Nano, 2025, 19(23): 21571-21588.

[90] 胡慧中, 郑晓君, 胡巧红. 姜黄素—甘草次酸-PEI-PLGA纳米粒的制备及工艺优化[J]. 山东医药, 2015, 55(16): 8-11.

[91] HU Huizhong, ZHENG Xiaojun, HU Qiaohong. Preparation of curcumin-glycyrrhetinic acid-PEI-PLGA nanoparticles and the process optimization[J]. Shandong Medical Journal, 2015, 55(16): 8-11.

[92] Silva PM, Gonçalves C, Pastrana LM, et al. Recent advances in oral delivery systems of resveratrol: foreseeing their use in functional foods[J]. Food Funct, 2023, 14(23): 10286-10313.

[93] Feng T, Wei Y, Lee RJ, et al. Liposomal curcumin and its application in cancer[J]. Int J Nanomedicine, 2017, 12: 6027-6044.

[94] Chen HW, Chen SD, Wu HT, et al. Improvement in curcumin’s stability and release by formulation in flexible nano-liposomes[J]. Nanomaterials, 2024, 14(22): 1836.

[95] Isailović BD, Kostić IT, Zvonar A, et al. Resveratrol loaded liposomes produced by different techniques[J]. Innov Food Sci Emerg Technol, 2013, 19: 181-189.

[96] Xiao Y, Ho CT, Chen Y, et al. Synthesis, characterization, and evaluation of genistein-loaded zein/carboxymethyl chitosan nanoparticles with improved water dispersibility, enhanced antioxidant activity, and controlled release property[J]. Foods, 2020, 9(11): 1604.

[97] Munot N, Kandekar U, Giram PS, et al. A comparative study of quercetin-loaded nanocochleates and liposomes: formulation, characterization, assessment of degradation and in vitro anticancer potential[J]. Pharmaceutics, 2022, 14(8): 1601.

[98] Zhong C, Luo S, Xiong R, et al. A new green self-assembly strategy for preparing curcumin-loaded starch nanoparticles based on natural deep eutectic solvent: Development, characterization and stability[J]. Food Hydrocoll, 2024, 151: 109878.

[99] 刘艳菊, 武月丹, 位小杰, 等. 包载金丝桃苷的磷脂酰胆碱/壳聚糖自组装纳米粒的制备、表征及其口服药动学研究[J]. 中草药, 2025, 56(3): 819-830.

[100] LIU Yanju, WU Yuedan, WEI Xiaojie, et al. Self-assembled phosphatidylcholine/chitosan nanoparticles loaded with hyperoside: Preparation, characterization and oral pharmacokinetics[J]. Chinese Traditional and Herbal Drugs, 2025, 56(3): 819-830.

[101] 冯丽珍, 黄锦平, 刘胜君, 等. 甘草酸、姜黄素和羟基喜树碱自组装纳米粒递药系统的工艺优化研究[J]. 广西医科大学学报, 2024, 41(4): 598-607.

[102] FENG Lizhen, HUANG Jinping, LIU Shengjun, et al. Study on the process optimization of self-assembled nano-drug delivery system of glycyrrhizic acid, curcumin and hydroxycamptothecin[J]. Journal of Guangxi Medical University, 2024, 41(4): 598-607.

[103] 许沙沙. 蛋白质—多糖自组装纳米凝胶基药物递送系统构建与表征[D]. 武汉: 华中农业大学, 2013.

[104] XU Shasha. Preparation and characterization of protein-polysaccharide self-assembled nanogels-based drug delivery systems[D]. Wuhan: Huazhong Agricultural University, 2013.

[105] Umeda K, Kobayashi K, Yamada H. Nanomechanics of self-assembled surfactants revealed by frequency-modulation atomic force microscopy[J]. Nanoscale, 2022, 14(12): 4626-4634.

[106] de Sousa FDB, Scuracchio CH. The use of atomic force microscopy as an important technique to analyze the dispersion of nanometric fillers and morphology in nanocomposites and polymer blends based on elastomers[J]. Polímeros, 2014, 24(6): 661-672.

[107] 秦祉剑. 芍药甘草汤自组装纳米粒的分离及其抗小鼠银屑病的研究[D]. 合肥: 安徽医科大学, 2023.

[108] QIN Zhijian. Separation and anti-psoriasis effect in mice of self-assembled nanoparticles from Shaoyao Gancao decoction[D]. Hefei: Anhui Medical University, 2023.

[109] 邓翔, 朱煜文, 郑冀邢, 等. 波棱甲素-波棱多糖自组装纳米粒的制备及其肠吸收机制研究[J]. 中国中药杂志, 2025, 50(2): 404-412.

[110] DENG Xiang, ZHU Yuwen, ZHENG Jixing, et al. Preparation and intestinal absorption mechanism of herpetrione and Herpetospermum caudigerum polysaccharides based self-assembled nanoparticles[J]. China Journal of Chinese Materia Medica, 2025, 50(2): 404-412.

[111] Shin C, Choi J, Kwak D, et al. Evaluation of size distribution measurement methods for sub-100 nm colloidal silica nanoparticles and its application to CMP slurry[J/OL]. ECS J Solid State Sci Technol, 2019, 8(5): P3195-P3200[2025-10-01].

[112] 杨建正, 周涛, 张见营. 质谱在纳米材料成分及粒径分析中的应用[J]. 质谱学报, 2023, 44(6): 721-738.

[113] YANG Jianzheng, ZHOU Tao, ZHANG Jianying. Application of mass spectrometry in component and particle size analysis of nanomaterials[J]. Journal of Chinese Mass Spectrometry Society, 2023, 44(6): 721-738.

[114] de Jonge N, Ross FM. Electron microscopy of specimens in liquid[J]. Nat Nanotechnol, 2011, 6(11): 695-704.

[115] 宋思宇, 傅舒, 吴学渊, 等. 三黄泻心汤主要有效成分间自组装纳米粒的构建及其抗胃溃疡作用评价[J]. 中草药, 2025, 56(11): 3819-3830.

[116] SONG Siyu, FU Shu, WU Xueyuan, et al. Construction of self-assembled nanoparticles between main active ingredients of Sanhuang Xiexin Decoction and evaluation of its anti-gastric ulcer effect[J]. Chinese Traditional and Herbal Drugs, 2025, 56(11): 3819-3830.

[117] 孟雨婷, 薛玉叶, 刘燕, 等. 甘草新型自组装纳米粒的形成及抗炎作用评价[J]. 中草药, 2024, 55(9): 2912-2922.

[118] MENG Yuting, XUE Yuye, LIU Yan, et al. Formation of novel self-assembled nanoparticles of Glycyrrhiza uralensis and anti-inflammatory evaluation[J]. Chinese Traditional and Herbal Drugs, 2024, 55(9): 2912-2922.

[119] Bush MF, Hall Z, Giles K, et al. Collision cross sections of proteins and their complexes: a calibration framework and database for gas-phase structural biology[J]. Anal Chem, 2010, 82(22): 9557-9565.

[120] 王昊宇, 许慧敏, 常建桥, 等. 纳米药物在肿瘤治疗与临床应用的发展与挑战[J]. 中国科学: 化学, 2022, 52(6): 795-813.

[121] WANG Haoyu, XU Huimin, CHANG Jianqiao, et al. Development and challenge of nanomedicines in tumor treatment and clinical application[J]. Scientia Sinica Chimica, 2022, 52(6): 795-813.

[122] 陈泠希, 倪淑婷, 赵文洋, 等. 茴香酰胺修饰熊果酸自组装纳米粒制备及其通过调控CAFs抗恩杂鲁胺对前列腺癌耐药作用研究[J]. 中成药, 2025, 47(1): 28-35.

[123] CHEN Lingxi, NI Shuting, ZHAO Wenyang, et al. Preparation of anisamide-modified ursolic acid self-assembled nanoparticles and their anti-drug resistance effect of enzalutamide on prostate cancer via regulation of CAFs[J]. Chinese Traditional Patent Medicine, 2025, 47(1): 28-35.

[124] 吴淑洋, 杨晓琴, 成威键, 等. 葛根芩连汤成分间自组装纳米粒改善伊立替康所致肠毒性作用研究[J]. 中草药, 2024, 55(12): 3987-3997.

[125] WU Shuyang, YANG Xiaoqin, CHENG Weijian, et al. Improvement of irinotecan-induced enterotoxicity by self-assembled nanoparticles between components of Gegen Qinlian Decoction[J]. Chinese Traditional and Herbal Drugs, 2024, 55(12): 3987-3997.

[126] Bouchemal K, Mazzaferro S. How to conduct and interpret ITC experiments accurately for cyclodextrin-guest interactions[J]. Drug Discov Today, 2012, 17(11/12): 623-629.

[127] 刘晶晶, 殷果, 黄小玲, 等. 纳米药物研究现状[J]. 中国药业, 2025, 34(2): 1-6.

[128] LIU Jingjing, YIN Guo, HUANG Xiaoling, et al. Current research of nanomedicines[J]. China Pharmaceuticals, 2025, 34(2): 1-6.

[129] Yan T, Yuan W, Zhang L, et al. Natural flavonoid glycoside-based self-assembled nanoparticles for synergistic antibacterial activity and improved antioxidant properties[J]. J Drug Deliv Sci Technol, 2025, 105: 106583.

[130] Goyanes A, Chang H, Sedough D, et al. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing[J]. Int J Pharm, 2015, 496(2): 414-420.

[131] Chen DQ, Liu WJ, Pi QM, et al. Preparation of injectable GelMA nanoparticles-based 3D printed wound healing filler[J/OL]. J Control Release, 2017, 259: e23[2025-10-01].

[132] Mousavi SM, Khasi S, Bryant SL, et al. Comprehensive characterization and stability analysis of APTES- and SDS-modified graphene nanofluids for enhanced thermosiphon performance in geothermal systems[J]. Colloids Surf A Physicochem Eng Aspects, 2025, 727: 138231.

[133] Pouso MR, Melo BL, Gonçalves JJ, et al. Development of dual-crosslinked Pluronic F127/Chitosan injectable hydrogels incorporating graphene nanosystems for breast cancer photothermal therapy and antibacterial applications[J]. Eur J Pharm Biopharm, 2024, 203: 114476.

[134] Shan XT, Cai Y, Zhu BY, et al. Computer-aided design of self-assembled nanoparticles to enhance cancer chemoimmunotherapy via dual-modulation strategy[J/OL]. Adv Healthc Mater, 2025, 14(7): e2404261[2025-10-01].

[135] Luo GH, Jiang XC, Hu CX, et al. Artificial intelligence-powered nanomedicine[J]. Chem Soc Rev, 2026, 55(4): 2070-2119.

基金资助

四川省科技计划项目(2024YFFK0163)

中央高校基本科研业务费专项资金(2682025ZTPY049)

中央高校基本科研业务费专项资金(202510613077)

西南交通大学个性化实验项目(GX202516003┫。This work was supported by the Sichuan Province Science and Technology Plan Project ┣2024YFFK0163)

the Special Fund for Basic Scientific Research Operations in Central Universities(2682025ZTPY049)

the Special Fund for Basic Scientific Research Operations in Central Universities(202510613077)

the Southwest Jiaotong University Personalized Experiment Project(GX202516003)

China.开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(CC BY-NC-ND 4.0┫的方式)

China.开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(在任何媒介以任何形式复制、传播本作品┣https://creativecommons.org/licenses/by-nc-nd/4.0/)

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开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(CC BY-NC-ND 4.0)的方式，在任何媒介以任何形式复制、传播本作品(https://creativecommons.org/licenses/by-nc-nd/4.0/)。