Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors

作者：Huang, Xiaowan; Cao, Ziyang; Qian, Jieying; Ding, Tao; Wu, Yanxia; Zhang, Hao; Zhong, Suqin; Wang, Xiaoli; Ren, Xiaoguang; Zhang, Wang; Xu, Youcui; Yao, Guangyu; Wang, Xingwu; Yang, Xianzhu^*; Wen, Longping^*; Zhang, Yunjiao^*

来源：Nature Nanotechnology, 2024.

DOI：10.1038/s41565-023-01562-5

• GAIN-OF-FUNCTION
• UBIQUITINATION
• FATE

In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation. @@@ Protein degradation is a powerful tool for a range of applications and therapies. Here, a selective autophagy receptor mimetic against mutant p53 protein is developed to substantially elevate autophagy levels and to recognize and transport mutant proteins for autophagy-mediated degradation and anticancer effect.

• 单位
  Southern Medical University; 1; Guangdong General Hospital; Sun Yat-sen University