Abstract
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.
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Data availability
The main data that support the findings of this study are available within the paper and its supplementary information. All the relevant data acquired during the study are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Key R&D Program of China (2022YFA1205700 to X.Y.), the National Natural Science Foundation of China (T2222014 and 32071398 to Y.Z., 82150118 and 32171375 to L.W., U22A20156 and 51822302 to X.Y., 82202305 to J.Q., 52203163 to Z.C.), the Key R&D Program of Guangdong Province (2020B1515120096 and 2022B0202010002 to Y.Z., 2020B0101030006 to L.W.), the China Postdoctoral Science Foundation (2023M741211 to X.H. and 2023T160230 to J.Q.), Basic and Applied Basic Research of Guangzhou (2023A04J1821 to J.Q.) and the Major Science and Technology projects in the Xinjiang Uygur Autonomous Region (2022A02004 to Y.Z.).
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Contributions
X.H., Z.C. and J.Q. designed and performed the majority of experiments, analysed the data and wrote the manuscript. T.D. helped detect the SPR of proteins. Y.W. and H.Z. constructed the related plasmids. S.Z., Xiaoli Wang, X.R., W.Z. and Y.X. helped construct the animal models. G.Y provided samples for establishing PDX models. Xingwu Wang provided important support to carry out the in vitro ubiquitination experiment. Y.Z., L.W. and X.Y. conceived the idea, designed the study, interpreted data and revised the final manuscript.
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Competing interests
Y.Z., X.H., Z.C., X.Y. and L.W. have submitted two patent applications (202211119762.4, PCT/CN2023/113588) related to this study. The other authors declare no competing interests.
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Nature Nanotechnology thanks Peter Tsevtkov and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary information
Supplementary Information
Supplementary methods, Figs. 1–45 and Tables 1–3.
Supplementary Video 1
Video of live EGFP–LC3/MDA-MB-231 cells co-incubated with Cy5-labelled mNRs for 2 h. Red, mNRs; green, LC3.
Supplementary Video 2
Video of live EGFP–LC3/MDA-MB-231 cells co-incubated with Cy5-labelled NRs for 2 h. Red, NRs; green, LC3.
Supplementary Data 1
Unprocessed western blots and/or gels for Supplementary Figs. 4, 15, 17, 20–24, 28, 29, 31, 34a and 41.
Source data
Source Data Figs. 2–6
Unprocessed western blots and/or gels for Figs. 2a,c,e,g–i, 3a,b,f,g,i–k, 4b, 5h and 6e.
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Huang, X., Cao, Z., Qian, J. et al. Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors. Nat. Nanotechnol. 19, 545–553 (2024). https://doi.org/10.1038/s41565-023-01562-5
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DOI: https://doi.org/10.1038/s41565-023-01562-5
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