Abstract
Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.
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Data availability
All data supporting the findings of this study are provided in the figures and supplementary materials. The sequencing data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus database under accession number GSE205833. Human liver transcriptome data were obtained from the Human Protein Atlas v.20.1. Statistical source data for all figures and supplementary figures are provided with this paper. Additional information can be requested from the corresponding authors (W.J., B.Y.S.K., H.W.). All equipment and reagents are commercially available and are described in the Methods section. Source data are provided with this paper.
Code availability
All the codes used in this study are open source and are accessible to the public. The R packages used are indicated in the Methods.
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Acknowledgements
The authors thank C. F. Wogan of the Division of Radiation Oncology at MD Anderson Cancer Center for editing this manuscript. The authors thank B. Q. Tran and S. A. Martinez at MD Anderson’s Metabolomics Facility for assisting with the mass spectrometry experiment and data analysis; J. Zhang of MD Anderson’s Department of Experimental Radiation Oncology for processing histologic samples; V. Van and K. L. Maldonado at MD Anderson’s Small Animal Imaging Facility for helping with the animal experiments; N. R. Vaughn and N. Nguyen at MD Anderson’s Flow Cytometry and Cellular Imaging Core Facility for helping with flow cytometry experiments; E. Parks at the UT Southwestern Medical Center for performing some of the in vitro experiments; and C. Yang at Washington University in St Louis for helping with bulk RNA-seq analysis. This work was supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT) (RR180017, W.J.) and Radiation Oncology Institute (N.N.S. and W.J.). This work was also supported in part by National Institutes of Health grant P30CA016672 (principal investigator, P. Pisters).
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W.J., B.Y.S.K., H.W. and Y.W. conceived the project and were responsible for all phases of the research. Y.W., W.D., D.L., L.Y., R.Y., H.W., B.Y.S.K. and W.J. designed the experiments. Y.W., D.L., L.Y., X.L., Y.L., M.Y., A.A., P.G., S.D., K.H., J.H., R.Y., L.T. and F.Z. performed the experiments and collected the data. W.D., L.Y. and Y.Z. performed bioinformatics and statistical analysis. Y.W., W.D., L.Y., X.L., Z.Y., M.Y., P.G., S.D., R.Y., K.H., B.R.S., M.K., Y.L., L.T., P.L.L., T.D.G., S.K.T., Y.Z., J.L., N.N.S. and W.J. analysed and interpreted the data. The manuscript was drafted by Y.W., W.D., L.Y., H.W., B.Y.S.K. and W.J. and was revised and approved by all authors.
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A provisional patent application based on the technology described in the manuscript has been filed by the Board of Regents, The University of Texas System, with W.J., Y.W. and B.Y.S.K. as inventors. The other authors declare no competing interests.
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Supplementary Figs. 1–51 and Table 1.
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Statistical source data of supplementary figures and differentially expressed genes identified in single-cell sequencing
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Wang, Y., Deng, W., Lee, D. et al. Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics. Nat. Nanotechnol. 19, 255–263 (2024). https://doi.org/10.1038/s41565-023-01502-3
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DOI: https://doi.org/10.1038/s41565-023-01502-3
