Abstract
A successful therapeutic outcome in the treatment of solid tumours requires efficient intratumoural drug accumulation and retention. Here we demonstrate that zinc gluconate in oral supplements assembles with plasma proteins to form ZnO nanoparticles that selectively accumulate into papillary Caki-2 renal tumours and promote the recruitment of dendritic cells and cytotoxic CD8+ T cells to tumour tissues. Renal tumour targeting is mediated by the preferential binding of zinc ions to metallothionein-1X proteins, which are constitutively overexpressed in Caki-2 renal tumour cells. This binding event further upregulates intracellular metallothionein-1X expression to induce additional nanoparticle binding and retention. In both tumour animal models and human renal tumour samples, we show that ZnO nanoparticles actively cross the vascular wall to achieve high intratumoural accumulation. We further explore this feature of ZnO nanoparticles for the delivery of chemotherapeutics to mouse and rabbit cancer models. Our findings demonstrate that ZnO nanoparticles derived from supplements can serve as a multifunctional drug delivery and cancer immunotherapy platform.
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Data availability
The sequence of MT-1X (KO and WT) was uploaded to GenBank (no. 2876090). The sequence of METTL3 (KO and WT) was uploaded to BioSample (nos. SAMN44109054, SAMN44109055 and SAMN44109056). The identification of proteins by MS is available at PRIDE (nos. PXD056522, PXD056393, PXD056379 and PXD056394). The raw sequence data (RNA m6A modification and RRBS of the RCC cell lines) have been deposited in the Genome Sequence Archive (GSA-Human, HRA008858). Single-cell RNA sequencing data were downloaded from published data at the European Genome-Phenome Archive (EGAS00001002325). The remaining data supporting the findings reported in this paper are available from the corresponding authors upon request.
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Acknowledgements
We thank H. Yin from Wuhan University for his valuable discussions and advice. We are also grateful to T. Zhou from Westlake University for his insightful suggestions on immune-related data analysis. This work was financially supported by the National Key R&D Program of China (nos. 2023YFC3403100 and 2022YFA1207300) (S.L.), the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB36000000) (G.N.), the National Natural Science Foundation of China (no. 82073392) (X.Z.) and (no. 82472141) (S.L.), the Jiangsu Provincial Key Research and Development Program (BE2021613) (X.Z.) and the CAS Project for Young Scientists in Basic Research (no. YSBR-036) (S.L.).
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X.Z., Z.Z.W., A.Z. and Y.W. performed the experiments. G.Z., S.L., G.N., T.W. and A.Z. conceived and designed the experiments. S.L., G.Z., G.N., A.Z. and T.W. wrote and revised the manuscript. A.W., Q.W., X.X., X.C. and W.Z. performed the experiments of the animal and nanocrystal experiments. B.L., Z.L., Q.L., G.L., Z.Z., F.W. and Y.Z. analysed the data of the biocompatibility of NPs and designed the mechanism scheme. A.Z. and Z.P.W. collected the patient tumour samples and blood. All authors discussed the results.
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Supplementary Figs. 1–70, Tables 1–3 and Western blot and gel images.
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Formation of an endocytic vesicle and the uptake of ZnO NPs.
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Degradation of ZnO NPs in lysosomes.
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Distribution of ZnO NPs from blood vessels to the surrounding tissue.
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Zeng, X., Wang, Z., Zhao, A. et al. Zinc nanoparticles from oral supplements accumulate in renal tumours and stimulate antitumour immune responses. Nat. Mater. 24, 287–296 (2025). https://doi.org/10.1038/s41563-024-02093-7
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DOI: https://doi.org/10.1038/s41563-024-02093-7
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