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Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics


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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Fig. 1: Age disparities in the effectiveness of cancer nanomedicine.
Fig. 2: Single-cell RNA-seq reveals ageing-associated changes in liver macrophages.
Fig. 3: Expression of MARCO on liver macrophages is decreased with ageing.
Fig. 4: MARCO expression is associated with nanoparticle uptake by macrophages.
Fig. 5: Blocking MARCO–nanoparticle interactions increases the effectiveness of therapeutic nanoparticles in young mice.

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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.


  1. de Magalhaes, J. P. How ageing processes influence cancer. Nat. Rev. Cancer 13, 357–365 (2013).

    Article  PubMed  Google Scholar 

  2. Laconi, E., Marongiu, F. & DeGregori, J. Cancer as a disease of old age: changing mutational and microenvironmental landscapes. Br. J. Cancer 122, 943–952 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Van Herck, Y. et al. Is cancer biology different in older patients? Lancet Healthy Longev. 2, E663–E677 (2021).

    Article  PubMed  Google Scholar 

  4. Sceneay, J. et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 9, 1208–1227 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  6. Kim, B. Y., Rutka, J. T. & Chan, W. C. Nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng 1, 0029 (2017).

    Article  CAS  Google Scholar 

  8. Rodriguez, P. L. et al. Minimal ‘self’ peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339, 971–975 (2013).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  9. Parodi, A. et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotechnol. 8, 61–68 (2013).

    Article  CAS  PubMed  ADS  Google Scholar 

  10. Gradishar, W. J. et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol. 23, 7794–7803 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Barenholz, Y. Doxil®—the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ngo, W. et al. Identifying cell receptors for the nanoparticle protein corona using genome screens. Nat. Chem. Biol. 18, 1023–1031 (2022).

    Article  CAS  PubMed  Google Scholar 

  15. Boehnke, N. et al. Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery. Science 377, eabm5551 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dobrowolski, C. et al. Nanoparticle single-cell multiomic readouts reveal that cell heterogeneity influences lipid nanoparticle-mediated messenger RNA delivery. Nat. Nanotechnol. 17, 871–879 (2022).

    Article  CAS  PubMed  ADS  Google Scholar 

  17. Jiang, W., Wang, Y., Wargo, J. A., Lang, F. F. & Kim, B. Y. S. Considerations for designing preclinical cancer immune nanomedicine studies. Nat. Nanotechnol. 16, 6–15 (2021).

    Article  PubMed  ADS  Google Scholar 

  18. Ouyang, B. et al. The dose threshold for nanoparticle tumour delivery. Nat. Mater. 19, 1362–1371 (2020).

    Article  CAS  PubMed  ADS  Google Scholar 

  19. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 1–12 (2016).

    Article  Google Scholar 

  20. Chen, Y. et al. Therapeutic remodeling of the tumor microenvironment enhances nanoparticle delivery. Adv. Sci. (Weinh.) 6, 1802070 (2019).

    PubMed  Google Scholar 

  21. Pili, R. et al. Altered angiogenesis underlying age-dependent changes in tumor growth. J. Natl Cancer Inst. 86, 1303–1314 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Marinho, A., Soares, R., Ferro, J., Lacerda, M. & Schmitt, F. C. Angiogenesis in breast cancer is related to age but not to other prognostic parameters. Pathol. Res. Pract. 193, 267–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Ouyang, B. et al. Impact of tumor barriers on nanoparticle delivery to macrophages. Mol. Pharm. 19, 1917–1925 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Grolleau, A., Misek, D. E., Kuick, R., Hanash, S. & Mule, J. J. Inducible expression of macrophage receptor Marco by dendritic cells following phagocytic uptake of dead cells uncovered by oligonucleotide arrays. J. Immunol. 171, 2879–2888 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Hamilton, R. F. Jr., Thakur, S. A., Mayfair, J. K. & Holian, A. MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice. J. Biol. Chem. 281, 34218–34226 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Park, J. et al. Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury. Proc. Natl Acad. Sci. USA 116, 14947–14954 (2019).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  27. Pikkarainen, T., Brannstrom, A. & Tryggvason, K. Expression of macrophage MARCO receptor induces formation of dendritic plasma membrane processes. J. Biol. Chem. 274, 10975–10982 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Hirano, S., Fujitani, Y., Furuyama, A. & Kanno, S. Macrophage receptor with collagenous structure (MARCO) is a dynamic adhesive molecule that enhances uptake of carbon nanotubes by CHO-K1 cells. Toxicol. Appl Pharm. 259, 96–103 (2012).

    Article  CAS  Google Scholar 

  29. van der Laan, L. J. et al. Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo. J. Immunol. 162, 939–947 (1999).

    Article  PubMed  Google Scholar 

  30. Arredouani, M. S. et al. MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages. J. Immunol. 175, 6058–6064 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Li, Z. et al. Aging-impaired filamentous actin polymerization signaling reduces alveolar macrophage phagocytosis of bacteria. J. Immunol. 199, 3176–3186 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Ojala, J. R., Pikkarainen, T., Tuuttila, A., Sandalova, T. & Tryggvason, K. Crystal structure of the cysteine-rich domain of scavenger receptor MARCO reveals the presence of a basic and an acidic cluster that both contribute to ligand recognition. J. Biol. Chem. 282, 16654–16666 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Novakowski, K. E. et al. A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function. Immunol. Cell Biol. 94, 646–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brannstrom, A., Sankala, M., Tryggvason, K. & Pikkarainen, T. Arginine residues in domain V have a central role for bacteria-binding activity of macrophage scavenger receptor MARCO. Biochem. Biophys. Res. Commun. 290, 1462–1469 (2002).

    Article  PubMed  Google Scholar 

  35. Wang, Y. et al. Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 5744–5756 (2018).

    Article  CAS  PubMed  ADS  Google Scholar 

  36. Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tabula Sapiens Consortium. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).

    Article  Google Scholar 

  38. Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article  PubMed  Google Scholar 

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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).

Author information

Authors and Affiliations



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.

Corresponding authors

Correspondence to Hongmei Wang, Betty Y. S. Kim or Wen Jiang.

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Competing interests

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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Nature Nanotechnology thanks Dennis Discher and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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Unprocessed blots

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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).

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