Details

Autor(en) / Beteiligte

• Qiao, Gongxi
• Pan, Xuming
• He, Mengyun
• Peng, Ruixi
• Huang, Xiangrong
• Nie, Cunpeng
• Jiang, Jianhui
• Chu, Xia

Titel

An ultrathin Zn-based layered double hydroxides augment degradation of mutant p53 to improve tumor therapy

Ist Teil von

• Chemical engineering journal (Lausanne, Switzerland : 1996), 2023-11, Vol.475, p.146449, Article 146449

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• •Zn-LDH@GOX degraded mutp53 across multiple mutant categories.•Zn2+ recovered wtp53 conformation and induced the mutp53 degradation through autophagy.•GOX disrupts the HSP90/mutp53 complex, leading to mutp53 degradation via ubiquitination-mediated proteasomal pathway.•Zn-LDH and GOX displayed the mutually synergistic degradation of mutp53 and inhibition of tumor growth in vivo. Tumor protein 53 (Tp53), a key regulator of suppressor genes, is commonly mutated in numerous malignant diseases. Consequently, elimination mutant protein 53 (mutp53) represents an appealing strategy for treating mutp53-related tumors. However, the treatment of these mutations remained challenging due to its formidable limitations. In this study, by loading glucose oxidase (GOX) into Zn-based layered double hydroxides (Zn-LDH) interlayer, a pH-responsive ultrathin nanotherapeutic platform (Zn-LDH@GOX) was created to suppress tumors growth by degrading mutp53. Upon exposure to the acidic environment of lysosomes, the lattice structure of Zn-LDH@GOX was partially disrupted, leading to the release of Zn2+ ions and GOX into the cytoplasm. The increased intracellular concentration of Zn2+ facilitated the restoration of wild-type protein 53 (wtp53) conformation, which in turn degraded mutp53 through activated autophagic pathways. Meanwhile, GOX-induced Heat Shock Protein 90 (HSP90) disruption resulted in the liberation of mutp53 from the HSP90/mutp53 complex and reactivated its degradation via the ubiquitination-mediated proteasomal pathway. In vitro and in vivo experiments confirmed the significant suppression of mutp53 expression and inhibition of tumor growth by Zn-LDH@GOX. Our work offers a novel pH-responsive nanotherapeutic platform with immense potential for mutp53 tumor-specific therapy.