<br>激光点燃脂质过氧化纳米放大器通过加剧铁死亡传播和可持续的高免疫原性来加强肿瘤光动力治疗,Small

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激光点燃脂质过氧化纳米放大器通过加剧铁死亡传播和可持续的高免疫原性来加强肿瘤光动力治疗
Small ( IF 13.0 ) Pub Date : 2023-11-22 , DOI: 10.1002/smll.202306402
Yunong Ma _{1,

2} , Xi Zhao ₁ , Peilin Tian ₁ , Kexin Xu ₁ , Jiayang Luo ₁ , Honghui Li ₂ , Mingqing Yuan ₁ , Xu Liu ₁ , Yanping Zhong ₃ , Pingzhen Wei ₃ , Jiaxing Song ₃ , Liewei Wen ₂ , Cuixia Lu _{1,

4}

Affiliation

光动力疗法（PDT）在临床肿瘤治疗中得到了广泛的研究。然而，光动力疗法的疗效受到光的组织穿透性、活性氧（ROS）的有效半衰期和半径短以及免疫刺激作用弱的严重限制。在这项研究中，开发了一种谷胱甘肽（GSH）激活的纳米光敏剂，负载花生四烯酸（AA）并通过红细胞膜进行伪装，作为激光点燃脂质过氧化纳米放大器（MAR）。 MAR的光敏效应随着肿瘤微环境的降解而恢复，并在激光激发下引发AA的过氧化。有趣的是，它在降解产物、亚铁离子（Fe ²⁺ ）和AA的参与下驱动连续的脂质过氧化链反应，从而加剧了癌细胞中铁死亡的传播。因此，即使没有光照的深层肿瘤细胞也会由于铁死亡信号的传播而发生铁死亡。而且，经历铁死亡的残余肿瘤细胞在PDT后仍保持较高的免疫原性，从而持续触发足够的肿瘤相关抗原（TAA）释放，显着促进抗肿瘤免疫反应。因此，本研究将提供一种新型的“一体式”纳米光敏剂，不仅可以放大PDT的损伤作用，扩大PDT的有效范围，还可以提高PDT后的免疫刺激效果。

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Laser-Ignited Lipid Peroxidation Nanoamplifiers for Strengthening Tumor Photodynamic Therapy Through Aggravating Ferroptotic Propagation and Sustainable High Immunogenicity

Photodynamic therapy (PDT) is extensively investigated for tumor therapy in the clinic. However, the efficacy of PDT is severely limited by the tissue penetrability of light, short effective half-life and radius of reactive oxygen species (ROS), and the weak immunostimulatory effect. In this study, a glutathione (GSH)-activatable nano-photosensitizer is developed to load with arachidonic acid (AA) and camouflage by erythrocyte membrane, which serves as a laser-ignited lipid peroxidation nanoamplifier (MAR). The photosensitive effect of MAR is recovered accompanied by the degradation in the tumor microenvironment and triggers the peroxidation of AA upon laser excitation. Interestingly, it aggravates the propagation of ferroptosis among cancer cells by driving the continuous lipid peroxidation chain reactions with the participation of the degradation products, ferrous ions (Fe²⁺), and AA. Consequently, even the deep-seated tumor cells without illumination also undergo ferroptosis owing to the propagation of ferroptotic signal. Moreover, the residual tumor cells undergoing ferroptosis still maintain high immunogenicity after PDT, thus continuously triggering sufficient tumor-associated antigens (TAAs) release to remarkably promote the anti-tumor immune response. Therefore, this study will provide a novel “all-in-one” nano-photosensitizer that not only amplifies the damaging effect and expands the effective range of PDT but also improves the immunostimulatory effect after PDT.

更新日期：2023-11-22

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