Acidity-Activatable Dynamic Nanoparticles Boosting Ferroptotic Cell Death for Immunotherapy of Cancer,Advanced Materials

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Acidity-Activatable Dynamic Nanoparticles Boosting Ferroptotic Cell Death for Immunotherapy of Cancer
Advanced Materials ( IF 27.4 ) Pub Date : 2021-06-25 , DOI: 10.1002/adma.202101155
Rundi Song ₁ , Tianliang Li ₁ , Jiayi Ye ₁ , Fang Sun ₁ , Bo Hou _{1,

2} , Madiha Saeed ₁ , Jing Gao ₁ , Yingjie Wang ₁ , Qiwen Zhu ₁ , Zhiai Xu ₂ , Haijun Yu ₁

Affiliation

Immunotherapy shows promising therapeutic potential for long-term tumor regression. However, current cancer immunotherapy displays a low response rate due to insufficient immunogenicity of the tumor cells. To address these challenges, herein, intracellular-acidity-activatable dynamic nanoparticles for eliciting immunogenicity by inducing ferroptosis of the tumor cells are engineered. The nanoparticles are engineered by integrating an ionizable block copolymer and acid-liable phenylboronate ester (PBE) dynamic covalent bonds for tumor-specific delivery of the ferroptosis inducer, a glutathione peroxidase 4 inhibitor RSL-3. The nanoparticles can stably encapsulate RSL-3 inside the hydrophobic core via π–π stacking interaction with the PBE groups at neutral pH (pH = 7.4), while releasing the payload in the endocytic vesicles (pH = 5.8–6.2) by acidity-triggered cleavage of the PBE dynamic covalent bonds. Furthermore, the nanoparticles can perform acid-activatable photodynamic therapy by protonation of the ionizable core, and significantly recruit tumor-infiltrating T lymphocytes for interferon gamma secretion, and thus sensitize the tumor cells to RSL-3-inducible ferroptosis. The combination of nanoparticle-induced ferroptosis and blockade of programmed death ligand 1 efficiently inhibits growth of B16-F10 melanoma tumor and lung metastasis of 4T1 breast tumors, suggesting the promising potential of ferroptosis induction for promoting cancer immunotherapy.

中文翻译：

酸激活动态纳米颗粒促进铁死亡细胞死亡，用于癌症免疫治疗

免疫疗法显示出长期肿瘤消退的有希望的治疗潜力。然而，由于肿瘤细胞的免疫原性不足，目前的癌症免疫疗法表现出较低的反应率。为了解决这些挑战，本文设计了细胞内酸度可激活的动态纳米颗粒，用于通过诱导肿瘤细胞的铁死亡来引发免疫原性。这些纳米粒子通过整合可电离的嵌段共聚物和酸不稳定的苯基硼酸酯 (PBE) 动态共价键进行设计，用于肿瘤特异性递送铁死亡诱导剂（谷胱甘肽过氧化物酶 4 抑制剂 RSL-3）。在中性pH值（pH = 7.4）下，纳米颗粒可以通过与PBE基团的π-π堆积相互作用将RSL-3稳定地封装在疏水核心内，同时通过酸度触发将有效负载释放到内吞囊泡（pH = 5.8-6.2）中。 PBE 动态共价键的裂解。此外，纳米粒子可以通过可电离核心的质子化进行酸激活光动力治疗，并显着招募肿瘤浸润T淋巴细胞分泌干扰素γ，从而使肿瘤细胞对RSL-3诱导的铁死亡敏感。纳米粒子诱导的铁死亡和程序性死亡配体1的阻断相结合，可有效抑制B16-F10黑色素瘤的生长和4T1乳腺肿瘤的肺转移，表明铁死亡诱导在促进癌症免疫治疗方面具有广阔的潜力。

更新日期：2021-08-05

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