Avidity-controlled biotherapeutic delivery systems for the treatment of acute kidney injury

Arielle Marie D'Elia

doi:10.17918/00011389

Kidney disease affects over 800 million people worldwide and represents a major and growing global health burden. Acute kidney injury (AKI), which occurs in over 50% of critically ill patients and affects more than 13 million individuals annually, is a significant predictor of in-hospital mortality and a major driver of progression to chronic kidney disease (CKD). The progression from AKI-to-CKD is driven by persistent inflammation and immune dysregulation, including impaired recruitment and differentiation of regulatory T cells (Tregs), which are essential for resolving inflammation and promoting tissue repair. While therapeutic proteins such as cytokines and chemokines offer high specificity and biocompatibility for immune modulation, their clinical utility is limited by rapid clearance, burst release, and a lack of spatiotemporal control over signaling. These challenges motivate the development of biomaterial-based delivery systems capable of sustained and localized presentation of immunoregulatory cues. To address these limitations, this work develops an injectable hydrogel platform for the avidity-based control of sustained biomolecule delivery. Supramolecular host-guest interactions between [beta]-cyclodextrin-based hydrogels and adamantane-modified proteins were leveraged to control biomolecule retention and release through synthetically tunable avidity. Methacrylated [beta]-cyclodextrin and dextran were co-polymerized to form mechanically robust hydrogels (G' ~15 kPa), which were processed into injectable granular hydrogels exhibiting shear-thinning (>90% reduction in storage modulus under strain) and rapid self-healing (>95% recovery within seconds). This platform enabled precise control over release kinetics, where increasing guest modification (up to 10 Ad per protein) attenuated burst release and extended biomolecule delivery for greater than one month. Building upon this delivery system, a dual-delivery immunomodulatory strategy was developed to recruit and program T cells in vivo. The chemokine CCL21 was selected for its ability to rapidly recruit CD4⁺ T cells, while adamantane-modified interleukin-2 (Ad-IL2) enabled sustained cytokine presentation to promote Treg differentiation and expansion. In vitro studies demonstrated that unmodified IL-2 exhibited rapid burst release (>90% release within 24 hours), whereas Ad-IL2 sustained release over 28 days while maintaining bioactivity. In vivo, subcutaneous delivery of CCL21 significantly increased CD4⁺ T cell recruitment within the first week, while Ad-IL2 increased Treg populations without inducing cytotoxic CD8⁺ T cell responses. Combination delivery of CCL21 and Ad-IL2 resulted in sustained expansion of Tregs within the hydrogel depot over 28 days, demonstrating the ability to coordinate immune cell recruitment and differentiation through temporally controlled signaling. This system was applied in a murine model of bilateral ischemia-reperfusion injury, which recapitulates key features of AKI-to-CKD progression. Hydrogel-mediated delivery of combined CCL21 and Ad-IL2 significantly improved renal function, as evidenced by increased transdermal glomerular filtration rate (tGFR) and decreased neutrophil gelatinase-associated lipocalin (NGAL), indicating reduced kidney injury. Immunofluorescence analysis further demonstrated over a 20-fold increase in FOXP3⁺ regulatory T cells and more than a 3-fold increase in CD206⁺ reparative macrophages in the combination treatment group, consistent with a shift toward a pro-regenerative immune microenvironment.

Avidity-controlled biotherapeutic delivery systems for the treatment of acute kidney injury

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Avidity-controlled biotherapeutic delivery systems for the treatment of acute kidney injury

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