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bioRxiv · 10.1101/2025.11.11.687837

Anti-CD3 microporous annealed particle hydrogel protects stem cell derived beta cells from autoreactive T cells

Widener, A. E.·Manson, C. T.·Barra, J. M.·Spencer, C. P.·Grodman, A. D.·Ladd, A. M.·Russ, H. A.·Phelps, E. A.
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Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic beta cells, leaving patients dependent on exogenous insulin and at risk of severe hypoglycemic episodes. Stem cell-derived beta-like cells (sBCs) offer a promising approach for beta cell replacement therapy, but clinical translation is limited by immune-mediated rejection, recurrent autoimmunity, and inhospitable transplantation sites. Biomaterials have been investigated to provide localized immune-isolation and immunomodulation, but foreign body responses and rapid depletion of therapeutic agents remain as obstacles to clinical translation. Here, we present a microporous annealed particle (MAP) hydrogel functionalized with an anti-CD3 monoclonal antibody (CD3) to provide a localized immunomodulatory microenvironment for beta cell replacement therapy. MAP hydrogels consisting of guest-host interlinked polyethylene glycol-maleimide (PEG-MAL) microgels supported rapid vascularization, minimal foreign body response, and engraftment of syngeneic islets in mice. CD3 MAP hydrogel halted T cell migration in vitro and protected transplanted sBCs from immune-mediated destruction by HLA-matched diabetogenic T cells in vivo. Subcutaneous CD3 functionalized MAP hydrogel also protected the endogenous islets in the pancreas, demonstrating potential for systemic immune modulation. These findings establish CD3 MAP hydrogels as a promising strategy for localized immune modulation in cell replacement therapy.

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Widener, A. E., Manson, C. T., Barra, J. M., Spencer, C. P., Grodman, A. D., Ladd, A. M., Russ, H. A., Phelps, E. A.. 2025-11-12. Anti-CD3 microporous annealed particle hydrogel protects stem cell derived beta cells from autoreactive T cells. https://doi.org/10.1101/2025.11.11.687837

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