Yan Yu, Lv Jie, Wang Mengqin, Xu Jie, Xia Yongzhi, Wei Ruiqi, Hua Lijuan, Xie Jun, Chen Yan
Department of Chemistry, Bengbu Medical University, Bengbu 233030, PR China.
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, PR China.
Colloids Surf B Biointerfaces. 2025 Nov;255:114913. doi: 10.1016/j.colsurfb.2025.114913. Epub 2025 Jun 26.
Despite their potential in cancer theranostics, silver nanoparticles (Ag NPs) face significant clinical translation challenges, including polydispersity, weak fluorescence emission, and suboptimal biocompatibility. To overcome these challenges, we introduce Ag@PEG2000-HA nanoclusters (NCs), novel silver-based NCs developed through a sequential functionalization process using polyethylene glycol (PEG) and hyaluronic acid (HA). The HA-induced stabilization enlarges nanocluster cores and promotes ligand-metal charge transfer, synergizing with size-dependent aggregation-induced emission (AIE) effect to amplify fluorescence. These developed nanoconstructs showcase enhanced theranostic capabilities, featuring strong near-infrared (NIR) fluorescence for live tumor imaging and reactive oxygen species (ROS)-enabled mitochondrial targeting to induce cancer cell apoptosis selectively. Systematic evaluations, both in vitro and in vivo, confirmed significant tumor growth inhibition, increased survival rates, and a positive biosafety profile. The dual-targeting approach, leveraging the enhanced permeability and retention (EPR) effect alongside HA-mediated CD44 interaction, ensures precise tumor targeting and reduces off-target effects. Additionally, the nanoclusters showed exceptional stability, extended blood circulation, and resistance to macrophage phagocytosis, thereby enhancing their therapeutic effectiveness. Detailed mechanistic studies showed that Ag@PEG2000-HA NCs trigger apoptosis via ROS production and mitochondrial disruption, and concurrently reduce the expression of key tumor-associated proteins (CD31, Ki-67, and MMP9), inhibiting angiogenesis, proliferation, and metastasis. This research establishes a multifunctional nanoplatform bridging diagnostic imaging and therapy, opening new avenues for precision oncology. The findings provide fundamental insights into the design principles of cluster-based theranostic nanomaterials, paving the way for their clinical translation in cancer treatment.
尽管银纳米颗粒（Ag NPs）在癌症诊疗方面具有潜力，但它们面临着重大的临床转化挑战，包括多分散性、弱荧光发射和欠佳的生物相容性。为了克服这些挑战，我们引入了Ag@PEG2000-HA纳米簇（NCs），这是一种通过使用聚乙二醇（PEG）和透明质酸（HA）的顺序功能化过程开发的新型银基纳米簇。HA诱导的稳定性扩大了纳米簇核心并促进配体-金属电荷转移，与尺寸依赖性聚集诱导发光（AIE）效应协同作用以增强荧光。这些开发的纳米结构展示出增强的诊疗能力，具有用于活体肿瘤成像的强近红外（NIR）荧光以及基于活性氧（ROS）的线粒体靶向，以选择性地诱导癌细胞凋亡。体外和体内的系统评估证实了显著的肿瘤生长抑制、提高的生存率和良好的生物安全性。这种双靶向方法利用增强的渗透和滞留（EPR）效应以及HA介导的CD44相互作用，确保精确的肿瘤靶向并减少脱靶效应。此外，纳米簇表现出卓越的稳定性、延长的血液循环和对巨噬细胞吞噬作用的抗性，从而提高了它们的治疗效果。详细的机理研究表明，Ag@PEG2000-HA NCs通过ROS产生和线粒体破坏触发凋亡，并同时降低关键肿瘤相关蛋白（CD31、Ki-67和MMP9）的表达，抑制血管生成、增殖和转移。这项研究建立了一个连接诊断成像和治疗的多功能纳米平台，为精准肿瘤学开辟了新途径。这些发现为基于簇的诊疗纳米材料的设计原则提供了基本见解，为它们在癌症治疗中的临床转化铺平了道路。
