Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury
- 1School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA
Abstract
Regulatory T cells (Tregs) are key mediators of immune resolution and tissue repair following acute kidney injury (AKI), yet strategies to selectively enrich Tregs within the renal microenvironment remain limited. Interleukin-2 (IL-2) is essential for Treg survival and function, but systemic IL-2 delivery is constrained by a short half-life, narrow therapeutic window, and risk of off-target activation of cytotoxic T cells. Effective Treg-based immunomodulation may therefore require both localized cytokine signaling and targeted recruitment of precursor immune populations. Here, we present a sequential, biomaterial-based immunomodulatory strategy that integrates immune cell recruitment with sustained cytokine delivery. An injectable granular hydrogel physically encapsulating the chemokine CCL21 was used to initially recruit CD4+ T cells to the injured kidney. Subsequently, supramolecular guest-host interactions were leveraged to deliver IL-2 modified with the hydrophobic "guest" moiety adamantane, enabling prolonged local cytokine release over 28 days. In healthy mice, we observed early CD4+ T cell recruitment, followed by a pronounced increase in Treg frequency, consistent with immune reprogramming driven by our sequential delivery system. In a murine model of bilateral ischemia-reperfusion (BiAKI), this injectable biomaterial induced a local increase in the proportion of FOXP3-expressing Tregs and a concomitant decrease in the levels of AKI markers. This two-step immunomodulatory approach minimizes acute immune activation while promoting long-term enrichment of Tregs within the renal microenvironment. Together, these findings demonstrate that granular hydrogels with supramolecular host capability can orchestrate immune recruitment and differentiation in a spatiotemporally controlled manner, providing a versatile immunomodulatory platform for applicability in kidney disease.
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BibTeX
@misc{delia2026aviditycontrolled,
title = {{Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury}},
author = {A. M. D'Elia and K. M. Kim and A. Shaw and S. Gholampoor and J. Friedrich and C. R. Russell and A. J. Seiner and A. R. Osidach and A. L. McSweeny and W. Gao and E. Adolay and S. Lynch and A. Stergar and E. Rajadhyaksha and B. Sarkar and D. E. Soranno and C. B. Rodell},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755753},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755753v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury
AU - A. M. D'Elia
AU - K. M. Kim
AU - A. Shaw
AU - S. Gholampoor
AU - J. Friedrich
AU - C. R. Russell
AU - A. J. Seiner
AU - A. R. Osidach
AU - A. L. McSweeny
AU - W. Gao
AU - E. Adolay
AU - S. Lynch
AU - A. Stergar
AU - E. Rajadhyaksha
AU - B. Sarkar
AU - D. E. Soranno
AU - C. B. Rodell
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755753
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755753v1
AB - Regulatory T cells (Tregs) are key mediators of immune resolution and tissue repair following acute kidney injury (AKI), yet strategies to selectively enrich Tregs within the renal microenvironment remain limited. Interleukin-2 (IL-2) is essential for Treg survival and function, but systemic IL-2 delivery is constrained by a short half-life, narrow therapeutic window, and risk of off-target activation of cytotoxic T cells. Effective Treg-based immunomodulation may therefore require both localized cytokine signaling and targeted recruitment of precursor immune populations. Here, we present a sequential, biomaterial-based immunomodulatory strategy that integrates immune cell recruitment with sustained cytokine delivery. An injectable granular hydrogel physically encapsulating the chemokine CCL21 was used to initially recruit CD4+ T cells to the injured kidney. Subsequently, supramolecular guest-host interactions were leveraged to deliver IL-2 modified with the hydrophobic "guest" moiety adamantane, enabling prolonged local cytokine release over 28 days. In healthy mice, we observed early CD4+ T cell recruitment, followed by a pronounced increase in Treg frequency, consistent with immune reprogramming driven by our sequential delivery system. In a murine model of bilateral ischemia-reperfusion (BiAKI), this injectable biomaterial induced a local increase in the proportion of FOXP3-expressing Tregs and a concomitant decrease in the levels of AKI markers. This two-step immunomodulatory approach minimizes acute immune activation while promoting long-term enrichment of Tregs within the renal microenvironment. Together, these findings demonstrate that granular hydrogels with supramolecular host capability can orchestrate immune recruitment and differentiation in a spatiotemporally controlled manner, providing a versatile immunomodulatory platform for applicability in kidney disease.
ER -