Lin Min, Liu Dandan, Gong Yiyu, Shu Lilei, Wang Helin, Zhang Guojing, Li Jiayi, Gao Zixin, Sun Jing, Chen Xuesi
State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, 130012 Changchun, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 130022 Changchun, China.
J Am Chem Soc. 2025 May 21;147(20):17010-17021. doi: 10.1021/jacs.5c01214. Epub 2025 May 12.
Natural bioactive pentacyclic triterpenoids, such as ursolic acid (UA), hold significant potential as anticancer agents. However, their clinical application is limited by their poor solubility and bioavailability. Herein, we developed a novel polypeptoid assembly cofactor-assisted nanoplatform designed to enhance UA's therapeutic efficacy through self-assembly within the tumor microenvironment (TME). Bioactive polypeptoid polyelectrolytes, inspired by natural molecular chaperones, were utilized as assembly cofactors to guide UA's co-assembly into stimuli-responsive nanostructures. These polypeptoids provide precise control over the assembly process, improving stability and enabling reversible, pH-responsive transformations. Acid-responsive groups and the target molecule lactobionic acid further promote the specificity and efficacy of UA delivery. Under neutral conditions, the assemblies retain a helical fibrous structure, while in the acidic TME, they transform into virus-like clusters composed of assembly subunits, facilitating deeper tumor penetration. Once internalized, these nanoparticles escape into the cytoplasm and accumulate around the mitochondria, where the oxidation of thioether bonds triggers the release of UA and polypeptoids, causing mitochondrial damage and apoptosis. Some nanoparticles reassemble into fibrous structures intracellularly, extending their retention in tumor cells and potentially leading to mitochondria damage. Notably, the nanoplatform demonstrates excellent synergistic effects, achieving significantly higher therapeutic efficiency compared with individual components, including UA and polypeptoids. studies further confirmed the effectiveness, demonstrating significant tumor growth suppression and reduced metastasis. By integrating the therapeutic UA with bioactive polypeptoids under precise control, this synergistic platform represents a highly efficient and targeted approach to cancer therapy, offering a promising new opportunity for natural compounds for advanced nanomedicine.
天然生物活性五环三萜类化合物，如熊果酸（UA），作为抗癌剂具有巨大潜力。然而，它们的临床应用受到其低溶解度和低生物利用度的限制。在此，我们开发了一种新型聚肽组装辅助纳米平台，旨在通过在肿瘤微环境（TME）中自组装来提高UA的治疗效果。受天然分子伴侣启发的生物活性聚肽聚电解质被用作组装辅助因子，以引导UA共组装成刺激响应性纳米结构。这些聚肽对组装过程提供精确控制，提高稳定性并实现可逆的、pH响应性转变。酸响应基团和靶向分子乳糖酸进一步促进了UA递送的特异性和有效性。在中性条件下，组装体保留螺旋纤维结构，而在酸性TME中，它们转变为由组装亚基组成的病毒样簇，促进更深的肿瘤渗透。一旦内化，这些纳米颗粒逃逸到细胞质中并聚集在线粒体周围，在那里硫醚键的氧化触发UA和聚肽的释放，导致线粒体损伤和细胞凋亡。一些纳米颗粒在细胞内重新组装成纤维结构，延长它们在肿瘤细胞中的保留时间并可能导致线粒体损伤。值得注意的是，该纳米平台显示出优异的协同效应，与包括UA和聚肽在内的单个组分相比，实现了显著更高的治疗效率。研究进一步证实了其有效性，证明了显著的肿瘤生长抑制和转移减少。通过在精确控制下将治疗性UA与生物活性聚肽整合，这种协同平台代表了一种高效且靶向的癌症治疗方法，为天然化合物用于先进纳米医学提供了一个有希望的新机会。
