Dual-target regulation of glutathione and heat shock proteins via molecular-carrier-pathway triple-engineering for potentiated phototherapy.

IF 12.2 2区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Materials Horizons Pub Date : 2025-05-27 DOI:10.1039/d5mh00614g

Yike Tu, Laiping Fang, Shufang Li, Kuo He, Yanzhao Diao, Lifeng Hang, Lina Wang, Jianan Dai, Ping'an Ma, Guihua Jiang

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Abstract

Photodynamic therapy (PDT) and photothermal therapy (PTT) face efficacy limitations due to overexpressed glutathione (GSH) and activated heat shock proteins (HSPs). Here, we synthesized a multifunctional agent N3-4F (N3) through molecular engineering. Leveraging strong acceptor-donor (A-D) interactions and reduced singlet-triplet energy gap (ΔE_S-T), N3 demonstrated exceptional type I/II reactive oxygen species (ROS) generation. An extended π-conjugated backbone with long alkyl chains enhanced light absorption and conferred a remarkable photothermal conversion efficiency (PCE) of 44.9%. To overcome tumor microenvironmental limitations, we engineered a disulfide bond-integrated nanocarrier and co-delivered HSP inhibitor KNK437 (437), selectively depleting intracellular GSH while disrupting thermoresistance. In vivo studies revealed that N3@437 under 808 nm laser irradiation achieved 94.9% tumor growth inhibition and markedly suppressed lung metastasis. By employing a triple-pronged strategy of molecular engineering, nanocarrier design, and pathway blockage, this work pioneered a paradigm that concurrently depletes GSH and inhibits HSPs. This breakthrough enables enhanced PDT/PTT performance, offering a transformative solution for combating tumor adaptive resistance.

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通过分子载体途径三重工程对谷胱甘肽和热休克蛋白的双靶标调控。

由于谷胱甘肽（GSH）和活化热休克蛋白（HSPs）的过度表达，光动力疗法（PDT）和光热疗法（PTT）面临疗效限制。本文采用分子工程技术合成了一种多功能药剂N3- 4f （N3）。利用强大的受体-供体（A-D）相互作用和减少的单重态-三重态能隙（ΔES-T）， N3表现出特殊的I/II型活性氧（ROS）生成。具有长烷基链的扩展π共轭骨架增强了光吸收，光热转换效率（PCE）达到44.9%。为了克服肿瘤微环境的限制，我们设计了一种二硫键集成纳米载体，并共同递送HSP抑制剂KNK437(437)，选择性地消耗细胞内GSH，同时破坏耐热性。体内研究表明，N3@437在808 nm激光照射下，肿瘤生长抑制率达到94.9%，并明显抑制肺转移。通过采用分子工程、纳米载体设计和通路阻断三管齐下的策略，这项工作开创了同时消耗谷胱甘肽和抑制热休克蛋白的范例。这一突破增强了PDT/PTT性能，为对抗肿瘤适应性抵抗提供了变革性的解决方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Materials Horizons CHEMISTRY, MULTIDISCIPLINARY-MATERIALS SCIENCE, MULTIDISCIPLINARY

CiteScore

18.90

自引率

2.30%

发文量

306

审稿时长

1.3 months

期刊介绍： Materials Horizons is a leading journal in materials science that focuses on publishing exceptionally high-quality and innovative research. The journal prioritizes original research that introduces new concepts or ways of thinking, rather than solely reporting technological advancements. However, groundbreaking articles featuring record-breaking material performance may also be published. To be considered for publication, the work must be of significant interest to our community-spanning readership. Starting from 2021, all articles published in Materials Horizons will be indexed in MEDLINE©. The journal publishes various types of articles, including Communications, Reviews, Opinion pieces, Focus articles, and Comments. It serves as a core journal for researchers from academia, government, and industry across all areas of materials research. Materials Horizons is a Transformative Journal and compliant with Plan S. It has an impact factor of 13.3 and is indexed in MEDLINE.