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Transport by circulating myeloid cells drives liposomal accumulation in inflamed synovium

Nature Nanotechnology volume 18, pages 1341–1350 (2023)Cite this article

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Abstract

The therapeutic potential of liposomes to deliver drugs into inflamed tissue is well documented. Liposomes are believed to largely transport drugs into inflamed joints by selective extravasation through endothelial gaps at the inflammatory sites, known as the enhanced permeation and retention effect. However, the potential of blood-circulating myeloid cells for the uptake and delivery of liposomes has been largely overlooked. Here we show that myeloid cells can transport liposomes to inflammatory sites in a collagen-induced arthritis model. It is shown that the selective depletion of the circulating myeloid cells reduces the accumulation of liposomes up to 50–60%, suggesting that myeloid-cell-mediated transport accounts for more than half of liposomal accumulation in inflamed regions. Although it is widely believed that PEGylation inhibits premature liposome clearance by the mononuclear phagocytic system, our data show that the long blood circulation times of PEGylated liposomes rather favours uptake by myeloid cells. This challenges the prevailing theory that synovial liposomal accumulation is primarily due to the enhanced permeation and retention effect and highlights the potential for other pathways of delivery in inflammatory diseases.

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Fig. 1: Characterization of the CIA model, the two different liposomes used in this study and their respective biodistribution over 24 h.
Fig. 2: Liposome engulfment by myeloid cells in CIA DBA/1 mice.
Fig. 3: Adoptive cell transfer experiment in C57BL/6 CIA mice.
Fig. 4: Liposome accumulation in myeloid-cell-depleted CIA mice.
Fig. 5: Physicochemical characterization and in vivo biodistribution of mRNA LNPs in CIA C57BL/6 mice.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Other relevant data are available for research purposes from the corresponding authors upon request. Source data are provided with this paper.

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Acknowledgements

J.D. acknowledges funding from the Special Research Fund (BOF) from Ghent University (grant no. 01D30517). R.V., S.M. and I.A. acknowledge funding from the Research Foundation-Flanders (FWO-V) (grant nos. 1275023N, 1S73120N and 1S40923N, respectively). I.L. and S.C.D.S acknowledge the FWO-V (grant agreement no. G016221N). I.L. acknowledges financial support from the Ghent University Special Research Fund (UGent-BOF) for Concerted Research Actions (GOA). The work of R.v.d.M. is supported by the Netherlands Research Council (NWO: ZonMW Vici grant no. 016.176.622 to W. J. M. Mulder). D.E. acknowledges funding from the FWO-V (grant nos. 3G0C7719, 3G067219 and G082023N) and Stichting tegen Kanker (STI) (grant no. STI.STK.2023.0005.01). We thank B.D and C.V. from the pre-clinical core imaging facility Infinity Lab (UGent).

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  1. These authors contributed equally: Dirk Elewaut, Ine Lentacker.

Authors and Affiliations

  1. Laboratory of General Biochemistry and Physical Pharmacy, Ghent Research Group on Nanomedicine, Ghent University, Ghent, Belgium

    Joke Deprez, Rein Verbeke, Sofie Meulewaeter, Ilke Aernout, Heleen Dewitte, Stefaan C. De Smedt & Ine Lentacker

  2. Cancer Research Institute Ghent (CRIG), Ghent, Belgium

    Joke Deprez, Rein Verbeke, Sofie Meulewaeter, Ilke Aernout, Heleen Dewitte, Stefaan C. De Smedt, Dirk Elewaut & Ine Lentacker

  3. Unit Molecular Immunology and Inflammation, VIB Centre for Inflammation Research, Ghent University and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium

    Joke Deprez, Tine Decruy, Julie Coudenys, Peggy Jacques & Dirk Elewaut

  4. VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium

    Julie Van Duyse & Gert Van Isterdael

  5. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Julie Van Duyse & Gert Van Isterdael

  6. Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Dan Peer

  7. Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel

    Dan Peer

  8. Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel

    Dan Peer

  9. Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel

    Dan Peer

  10. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands

    Roy van der Meel

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  1. Joke Deprez
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Contributions

I.L., D.E. and S.C.D.S. designed the project. J.D. was responsible for the protocols and project management. J.D., S.M. and I.A. carried out the liposome fabrication. J.D., R.V., S.M., I.A., H.D., T.D., J.C. and I.L. carried out the mice experiments. T.D. and J.C. were responsible for scoring, caretaking and harvesting the mice. J.D., R.V., S.M. and I.A. performed the IVIS imaging of the mice. J.V.D. and G.V.I. conducted the ImageStream experiments via the VIB Flow Core. J.D., I.L. and D.E. conceptualized the autologous transfusion experiment. J.D., D.P., S.M. and I.L. contributed to the conceptualization of the depletion experiment. J.D. analysed the data. R.v.d.M. helped with the fabrication and guidance of the mRNA LNPs. J.D., R.V. and I.L. wrote the manuscript with input from S.C.D.S, D.E., P.J. and R.v.d.M. All the authors contributed to the discussions and the final work.

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Correspondence to Dirk Elewaut or Ine Lentacker.

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Deprez, J., Verbeke, R., Meulewaeter, S. et al. Transport by circulating myeloid cells drives liposomal accumulation in inflamed synovium. Nat. Nanotechnol. 18, 1341–1350 (2023). https://doi.org/10.1038/s41565-023-01444-w

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