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TRIM21-dependent ultrasmall chiral gold nanoparticles for preventing microglia senescence against Alzheimer’s disease

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Abstract

Tripartite motif 21 (TRIM21) is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination. Here, ultrasmall chiral gold nanoparticles (D- or L-NPs) modified by D- or L-glutathione ligands were fabricated. After conjugated with an NLR family pyrin domain-containing protein 3 (NLRP3) antibody (D-NP-aNLRP3 or L-NP-aNLRP3), D-NP-aNLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence, and p16ink4a, a marker of senescence, in the microglia was reduced by 90.3% ± 7.8% while L-NP-aNLRP3 decreased by 48.01% ± 3.1%. Mechanistic investigations revealed that the D-NP-aNLRP3 ((1.5 ± 0.3) × 107 M−1) exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type ((9.5 ± 2.7) × 105 M−1), which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation. Notably, the blood-brain barrier (BBB)-crossing ability of chiral NP-aNLRP3 as well as NLRP3 degradation was demonstrated in vivo. The APP/PS1 Alzheimer’s disease (AD) model mice experiments exhibited a reduction of 89.7% ± 6.8% for the NLRP3 protein and 84.2 ± 7.5% for p16ink4a following the intravenous administration of D-NP-aNLRP3 once a week for 60 days. Furthermore, the levels of the AD markers Aβ and phosphorylated-Tau in the brains were reduced by 86.2% ± 8.2% and 81.6% ± 9.1%; these were 2.1-fold and 1.9-fold higher than those treated with L-NP-aNLRP3, respectively. The studies provide a method to rescue AD-like pathologies and prevent senescence.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (22274067, 82071187), the Natural Science Foundation of Jiangsu Province (BK20230043) and the Fundamental Research Funds for the Central Universities (JUSRP622009).

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Authors and Affiliations

  1. International Joint Research Laboratory for Biointerface and Biodetection, State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China

    Meiru Lu, Changlong Hao, Liguang Xu, Hua Kuang, Chuanlai Xu & Maozhong Sun

  2. Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, China

    Feng Yu

  3. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China

    Jiwei Jiang, Yanli Wang & Jun Xu

  4. National Clinical Research Center for Neurological Diseases, Beijing, 100070, China

    Jiwei Jiang, Yanli Wang & Jun Xu

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  1. Meiru Lu
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  2. Changlong Hao
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  3. Liguang Xu
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  4. Feng Yu
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  5. Jiwei Jiang
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  7. Jun Xu
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  9. Chuanlai Xu
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  10. Maozhong Sun
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Correspondence to Jun Xu or Maozhong Sun.

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Supporting information The supporting information is available online at chem.scichina.com and link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Lu, M., Hao, C., Xu, L. et al. TRIM21-dependent ultrasmall chiral gold nanoparticles for preventing microglia senescence against Alzheimer’s disease. Sci. China Chem. 67, 1360–1372 (2024). https://doi.org/10.1007/s11426-023-1859-4

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