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Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy

Abstract

Activation of scramblases is one of the mechanisms that regulates the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumour immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Based on this finding, we developed a nanocarrier for co-delivery of Xkr8 short interfering RNA and the FuOXP prodrug to tumours. Intravenous injection of our nanocarrier led to significant inhibition of tumour growth in colon and pancreatic cancer models along with increased antitumour immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers.

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Fig. 1: Xkr8 was induced by chemotherapeutic agents in vitro and in vivo.
Fig. 2: Development and biophysical characterization of PMBOP-CP-based nanocarrier for co-delivery of siXkr8 and FuOXP.
Fig. 3: Optimizing PMBOP-CP NPs for effective tumour targeting in vivo.
Fig. 4: CD44-mediated vascular targeting plays a role in tumour targeting.
Fig. 5: In vivo PK and tissue distribution of siXkr8 and FuOXP following intravenous administration of FuOXP/siXkr8 NPs, and the efficiency of gene knockdown.
Fig. 6: Biological consequences of Xkr8 knockdown in vitro and in vivo.

Data availability

The bulk messenger RNA-seq data mapped to the mouse genome (GRCm38: https://www.ncbi.nlm.nih.gov/assembly/GCF_000001635.20/) are available in the NCBI Gene Expression Omnibus (GEO) under accession number GSE214881 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214881). Source data are provided with this paper. All data generated or analysed during this study are included in this Article and its Supplementary Information files.

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Acknowledgements

This work was supported by National Institute of Health grants R01CA219399, R01CA223788 (to S.L.), R01CA219716 (to B.L. and S.L.) and a grant from the Shear Family Foundation. We thank R. Gibbs for his advice on statistical analysis.

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization, Y.C., Y.H. and S.L. Methodology, Y.C. and Y.H. Validation, Y.C., Y.H., Q.L., Z.L., Z.Z. and H.H. Formal analysis, Y.C. Investigation, Y.C., Y.H., Q.L., Z.L., Z.Z., H.H., J.S., L.Z., R.S., D.B., J.F.C., B.L. and S.L. Visualization, Y.C. and Y.H. Writing—original draft, Y.C. and S.L. Writing—review and editing, Y.C. and S.L. Project administration, Y.C. and S.L. Funding acquisition, S.L. Resources, S.L. Supervision, S.L. and B.L.

Corresponding authors

Correspondence to Binfeng Lu or Song Li.

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Nature Nanotechnology thanks Shigekazu Nagata, David Oupicky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Table of contents, Supplementary methods, Supplementary Figs. 1–24, Table 2 and references.

Reporting Summary

Supplementary Table 1

List of siRNA and primer sequences.

Source data

Source Data For Fig. 1

Unprocessed Western Blots for Fig. 1.

Source Data For Fig. 2

Unprocessed gels for Fig. 2.

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Chen, Y., Huang, Y., Li, Q. et al. Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy. Nat. Nanotechnol. (2022). https://doi.org/10.1038/s41565-022-01266-2

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