An ultrasensitive and modular platform to detect Siglec ligands and control immune cell function

Jame-Chenarboo, Z.; Schmidt, E. N.; Crichton, M.; Takahashi-Yamashiro, K.; Lima, G. M.; Luna-Dulcey, L.; Jung, J.; Ivison, S.; St. Laurent, C. D.; Enterina, J. R.; Lin, S.-Y.; Sarkar, S.; John, R.; Nanjappa, S. G.; Malaker, S. A.; Levings, M. K.; Marth, J. D.; Derda, R.; Macauley, M. S.

doi:10.1101/2025.06.10.658684

bioRxiv · 10.1101/2025.06.10.658684

An ultrasensitive and modular platform to detect Siglec ligands and control immune cell function

Jame-Chenarboo, Z.·Schmidt, E. N.·Crichton, M.·Takahashi-Yamashiro, K.·Lima, G. M.·Luna-Dulcey, L.·Jung, J.·Ivison, S.·St. Laurent, C. D.·Enterina, J. R.·Lin, S.-Y.·Sarkar, S.·John, R.·Nanjappa, S. G.·Malaker, S. A.·Levings, M. K.·Marth, J. D.·Derda, R.·Macauley, M. S.

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Abstract

Siglecs are immunomodulatory receptors that regulate immune cell function. A fundamental challenge in studying Siglec-ligand interactions is the low affinity of Siglecs for their ligands. Inspired by how nature uses multivalency, we developed Siglec-liposomes as a highly multivalent and versatile platform for detecting Siglec glycan ligands in which recombinant Siglecs were conjugated to liposomes using the SpyCatcher-SpyTag system. Siglec-liposomes offer tunable multivalency and a modular assembly, enabling presentation of different Siglecs on the same liposome. Using Siglec-liposomes, we profiled Siglec ligands on human leukocytes, revealing new insights into Siglec ligands. Moreover, Siglec-liposomes are in vivo compatible, where we demonstrated that Siglec-7-liposomes bind to the brain vasculature in a mucin-dependent manner. Given the abundance of Siglec ligands on T cells, we investigated whether Siglec-liposomes modulate T cell function and find that Siglec-7-liposomes increase T cell proliferation in a ST3Gal1-dependent and CD43-independent manner. Taken together, Siglec-liposomes are a versatile and sensitive tool for detecting Siglec ligands and immunomodulation.

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Jame-Chenarboo, Z., Schmidt, E. N., Crichton, M., Takahashi-Yamashiro, K., Lima, G. M., Luna-Dulcey, L., Jung, J., Ivison, S., St. Laurent, C. D., Enterina, J. R., Lin, S.-Y., Sarkar, S., John, R., Nanjappa, S. G., Malaker, S. A., Levings, M. K., Marth, J. D., Derda, R., Macauley, M. S.. 2025-06-12. An ultrasensitive and modular platform to detect Siglec ligands and control immune cell function. https://doi.org/10.1101/2025.06.10.658684

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