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声动力学治疗驱动的免疫治疗:使用先进的受体调控策略构建 AIE 有机声敏剂。

Sonodynamic Therapy-Driven Immunotherapy: Constructing AIE Organic Sonosensitizers Using an Advanced Receptor-Regulated Strategy.

机构信息

State Key Laboratory of Separation Membranes and Membrane Processes, School of Materials Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.

State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemical Engineering and Technology, Tiangong University, Tianjin, 300387, P. R. China.

出版信息

Small. 2024 Sep;20(37):e2400654. doi: 10.1002/smll.202400654. Epub 2024 May 16.

Abstract

Benefit from the deeper penetration of mechanical wave, ultrasound (US)-based sonodynamic therapy (SDT) executes gratifying efficacy in treating deep-seated tumors. Nevertheless, the complicated mechanism of SDT undeniably hinders the exploration of ingenious sonosensitizers. Herein, a receptor engineering strategy of aggregation-induced emission (AIE) sonosensitizers (TPA-Tpy) with acceptor (A)-donor (D)-A' structure is proposed, which inspects the effect of increased cationizations on US sensitivity. Under US stimulation, enhanced cationization in TPA-Tpy improves intramolecular charge transfer (ICT) and accelerates charge separation, which possesses a non-negligible promotion in type I reactive oxygen species (ROS) production. Moreover, abundant ROS-mediated mitochondrial oxidative stress triggers satisfactory immunogenic cell death (ICD), which further promotes the combination of SDT and ICD. Subsequently, subacid pH-activated nanoparticles (TPA-Tpy NPs) are constructed with charge-converting layer (2,3-dimethylmaleic anhydride-poly (allylamine hydrochloride)-polyethylene glycol (DMMA-PAH-PEG)) and TPA-Tpy, achieving the controllable release of sonosensitizers. In vivo, TPA-Tpy-mediated SDT effectively initiates the surface-exposed of calreticulin (ecto-CRT), dendritic cells (DCs) maturation, and CD8 T cell infiltration rate through enhanced ROS production, achieving suppression and ablation of primary and metastatic tumors. This study provides new opinions in regulating acceptors with eminent US sensitization, and brings a novel ICD sono-inducer based on SDT to realize superior antitumor effect.

摘要

得益于机械波的更深穿透性,基于超声的声动力学疗法(SDT)在治疗深部肿瘤方面表现出令人满意的疗效。然而,SDT 的复杂机制无疑阻碍了对巧妙声敏剂的探索。在此,提出了具有受体工程策略的聚集诱导发射(AIE)声敏剂(TPA-Tpy),其具有受体(A)-给体(D)-A'结构,研究了增加阳离子化对超声敏感性的影响。在超声刺激下,TPA-Tpy 中的增强阳离子化促进了分子内电荷转移(ICT)并加速了电荷分离,这对 I 型活性氧(ROS)的产生具有不可忽视的促进作用。此外,丰富的 ROS 介导的线粒体氧化应激引发了令人满意的免疫原性细胞死亡(ICD),进一步促进了 SDT 和 ICD 的结合。随后,构建了带电荷转换层(2,3-二甲基马来酸酐-聚(烯丙基胺盐酸盐)-聚乙二醇(DMMA-PAH-PEG)和 TPA-Tpy)的亚酸性 pH 激活纳米颗粒(TPA-Tpy NPs),实现了声敏剂的可控释放。在体内,TPA-Tpy 介导的 SDT 通过增强 ROS 的产生,有效地引发了 calreticulin(ecto-CRT)的表面暴露、树突状细胞(DC)成熟和 CD8 T 细胞浸润率,从而抑制和消融原发性和转移性肿瘤。本研究为调节具有卓越超声敏化作用的受体提供了新的观点,并带来了一种基于 SDT 的新型 ICD 声敏剂,以实现优异的抗肿瘤效果。

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