岩藻依聚糖修饰的金属唑来膦酸纳米复合物通过诱导铁死亡细胞死亡和增强癌症免疫疗法来抑制肿瘤转移。

Fucoidan-decorated metal-zoledronic acid nanocomplexes suppress tumor metastasis by inducing ferroptotic cell death and enhancing cancer immunotherapy.

作者信息

Tsai Hsin-Ting, Lin Chi, Chung Chu-Hung, Hsu Wen-Jing, Hsieh Ming-Yi, Chiang Ming-Cheng, Lu Tzu-Wei, Mi Fwu-Long, Lin Cheng-Wei

机构信息

Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei, 11031, Taiwan.

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.

出版信息

J Nanobiotechnology. 2025 Jun 2;23(1):405. doi: 10.1186/s12951-025-03473-0.

Abstract

Metastatic tumor cells that escape from immune surveillance are a dilemma in cancer treatment, and thus developing selective targeting agents to treat metastatic tumor and reinstate immune perception is imperative for clinical applications. Herein, a multifunctional nanoplatform of supramolecular assembled nanoparticles (SANs) comprising a core structure of metal ion (Fe) and organic ligands including tannic acid (TA), and zoledronic acid (Zol) was developed. The FTZ SANs was further decorated with fucoidan (Fu), a P-selectin ligand, which greatly enhanced specific binding affinity of FTZ@Fu SANs towards metastatic tumor cells and suppressed tumor aggressiveness. The Fe-TA-Zol coordination network constructed through competitive ligand substitution facilitated the releases of Zol in response to the acidic tumor microenvironment (TME), which also benefited iron redox cycling of the Fenton reaction and further trigger ferritinophagy. Subsequently, Zol coordinately exerted ferroptotic-inducing activity accompanied by induction of stimulator of interferon genes (STING) pathway to aggravate immunogenic cell death (ICD) and enhance the antitumor immune response. Furthermore, FTZ@Fu effectively attenuated the immunosuppressive TME to suppress tumor growth and distant metastasis, and FTZ@Fu potentiated the therapeutic efficacy in combination with immune checkpoint blockade (ICB) therapy. Importantly, FTZ@Fu SANs suppressed metastatic tumor growth and reshaped the immune microenvironment. Our nanosystem provides a promising avenue for synergetic cancer targeting and chemoimmunotherapy, paving the way for targeted therapeutic strategies.

摘要

逃脱免疫监视的转移性肿瘤细胞是癌症治疗中的一个难题,因此开发选择性靶向药物来治疗转移性肿瘤并恢复免疫识别对于临床应用至关重要。在此,我们开发了一种超分子组装纳米颗粒(SANs)的多功能纳米平台,其核心结构为金属离子(Fe),有机配体包括单宁酸(TA)和唑来膦酸(Zol)。FTZ SANs进一步用岩藻依聚糖(Fu)进行修饰,岩藻依聚糖是一种P-选择素配体,极大地增强了FTZ@Fu SANs对转移性肿瘤细胞的特异性结合亲和力,并抑制了肿瘤侵袭性。通过竞争性配体取代构建的Fe-TA-Zol配位网络促进了Zol在酸性肿瘤微环境(TME)中的释放,这也有利于芬顿反应的铁氧化还原循环,并进一步触发铁蛋白自噬。随后,Zol协同发挥铁死亡诱导活性,同时诱导干扰素基因刺激因子(STING)通路,加剧免疫原性细胞死亡(ICD)并增强抗肿瘤免疫反应。此外,FTZ@Fu有效地减弱了免疫抑制性TME以抑制肿瘤生长和远处转移,并且FTZ@Fu与免疫检查点阻断(ICB)疗法联合使用时增强了治疗效果。重要的是,FTZ@Fu SANs抑制了转移性肿瘤生长并重塑了免疫微环境。我们的纳米系统为协同癌症靶向和化学免疫疗法提供了一条有前景的途径,为靶向治疗策略铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e00/12128240/7090e734a724/12951_2025_3473_Fig1_HTML.jpg

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