The active targeting strategy has achieved inspiring progress for drug accumulation in tumor therapy; however, the insufficient expression level of many potential receptors poses challenges for drug delivery. Poly-γ-glutamic acid (γ-pGluA), a naturally occurring anionic biopolymer, showed high affinity with tumor-associated gamma-glutamyl transpeptidase (GGT), which localized on the cell surface and exhibited intracellular redox homeostasis-dependent expression pattern; thus, GGT was utilized for mediating endocytosis of nanoparticles. Herein, GGT-targeting nanopolyplexes (γ-pGluA-CSO@Fe³⁺, PCFN) consisting of cationic chitosan and GGT-targeting γ-pGluA blended with iron ion were constructed to load reactive oxygen species-induced menadione (MA) and doxorubicin, which were utilized to investigate the mechanism of GGT up-regulation. Briefly, the pretreated PCFN/MA induced an intracellular oxidative stress environment, which facilitated adjusted up-regulated GGT expression and boosted tumor targeting. Subsequently, the destroyed redox homeostasis sensitized tumors for synergistic therapy. The innovative strategy of augmenting active targeting by disturbing intracellular redox homeostasis offers insight for the application of γ-pGluA-derived nanopolyplexes.

中文翻译：

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聚-γ-谷氨酸衍生的纳米复合物，可通过调节细胞内氧化还原稳态来上调γ-谷氨酰转肽酶，从而增强肿瘤活性靶向并增强协同抗肿瘤治疗。

主动靶向策略已在肿瘤治疗中取得了令人鼓舞的药物积累进展；然而，许多潜在受体的表达水平不足为药物递送提出了挑战。天然存在的阴离子生物聚合物聚-γ-谷氨酸（γ-pGluA）对肿瘤相关的γ-谷氨酰转肽酶（GGT）具有高亲和力，后者位于细胞表面并表现出细胞内氧化还原稳态依赖的表达模式。因此，GGT被用于介导纳米颗粒的内吞。此处，靶向GGT的纳米复合物（γ-pGluA-CSO@ Fe ³⁺构建了由阳离子壳聚糖和靶向GGT的γ-pGluA与铁离子混合组成的PCFN，以负载活性氧诱导的甲萘醌（MA）和阿霉素，从而研究了GGT上调的机制。简而言之，预处理的PCFN / MA诱导了细胞内氧化应激环境，这有助于调节上调的GGT表达并促进肿瘤靶向。随后，被破坏的氧化还原稳态使致敏肿瘤用于协同治疗。通过扰乱细胞内氧化还原稳态来增强主动靶向的创新策略为从γ-pGluA衍生的纳米复合物的应用提供了见识。