{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:53:32Z","timestamp":1791294812235,"version":"4.1.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Bioengineering","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R35GM147184"],"award-info":[{"award-number":["R35GM147184"]}]},{"award":["Startup Funds"],"award-info":[{"award-number":["Startup Funds"]}],"id":[{"id":"https:\/\/ror.org\/04bdffz58","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 AR069619"],"award-info":[{"award-number":["P30 AR069619"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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\u2013host interactions were leveraged to deliver IL-2 modified with the hydrophobic \u201cguest\u201d 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\u2013reperfusion (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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Acute kidney injury (AKI)-induced inflammation perpetuates renal failure.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Regulatory T cells (Tregs) are renoprotective post-AKI.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Granular hydrogels with supramolecular (host) functionality were designed.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Fast release of CCL21 and slow release of modified IL-2 was achieved.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Dual-release induced abundant Tregs, protecting against kidney injury.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.755753","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:40:17Z","timestamp":1790930417000},"source":"Crossref","is-referenced-by-count":0,"title":["Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury"],"prefix":"10.64898","author":[{"given":"Arielle M.","family":"D\u2019Elia","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M.","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Medicine, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alle\u00e9","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayeh","family":"Gholampoor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Carl R.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari J.","family":"Seiner","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R.","family":"Osidach","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail L.","family":"McSweeny","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winni","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Medicine, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Adolay","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angus","family":"Stergar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Rajadhyaksha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9298-2392","authenticated-orcid":false,"given":"Biplab","family":"Sarkar","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-809X","authenticated-orcid":false,"given":"Danielle E.","family":"Soranno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA"},{"name":"Department of Biomedical Engineering, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-0802","authenticated-orcid":false,"given":"Christopher B.","family":"Rodell","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Sciences, Drexel University, Philadelphia, PA, USA"},{"name":"Department of Microbiology & Immunology, College of Medicine, Drexel University, Philadelphia, 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