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Injectable acellular hydrogels for local immunoregulation and tolerance

Award Number: R21AI199487
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/24/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Injectable acellular hydrogels for local immunoregulation and tolerance - PROJECT SUMMARY Autoimmune diseases afflict more than 15 million Americans, one-third of which have two or more autoimmune conditions. An elevated abundance of pro-inflammatory and/or autoreactive T cells (Teff) and reduced levels of regulatory T cells (Tregs) underlies disease onset, progression, and the common relapsing-and-remitting nature of symptoms. Medical management of autoimmune conditions focuses on systemic immunosuppression; though, it is a suboptimal solution that i) addressed symptoms but is not curative and ii) precipitates risk of opportunistic infection and tumorigenesis. Hence, there is an urgent need to re-establish homeostatic Teff/Tregs function in order to regulate chronic inflammation and reinstate antigen-specific self-tolerance – which would be a Holy Grail for autoimmune therapies. There remains, however, no safe and effective therapy to procure and maintain Tregs. Treg-directed therapies have focused primarily on in vivo Treg induction via delivery of soluble factors or adoptive cell transfer, but these techniques are limited by 1) impurities of autoreactive and pro- inflammatory T cells, 2) phenotypic instability of induced Tregs, 3) challenges in controlled drug delivery, and 4) off-target effects. These drawbacks have motivated us to develop an injectable granular hydrogel that induces T regs and complements their cellular memory through co-inhibitory signaling. The hydrogel enables the localized presentation of an onco-fetal immune checkpoint, B7x, covalently tethered through azide-alkyne click chemistry. Functionally, B7x both inhibits Teff differentiation and function as well as induces Tregs and bolsters their function. Our preliminary data demonstrate that C-terminal azide modification of B7x does not detrimentally affect it’s ability to induce Tregs. Subcutaneous injection of B7x-conjugated hydrogels in mice increased local Treg abundance and mitigated psoriasis in pilot studies. We hypothesize that the B7x-conjugated granular hydrogels will alleviate local inflammation by expanding Treg populations thereby creating an immunoregulatory niche that, when coupled with the delivery of disease-specific self-antigens, will foster tolerance and mitigate the autoimmune response. This hypothesis will be examined through two aims. In the imiquimod-induced psoriasis model, we will first determine if B7x-conjugated hydrogels induce Tregs and mitigate Teff response through immunoregulatory mechanisms. In the second aim, we will examine if the co-delivery of disease-specific antigens within this immunoregulatory niche will foster tolerance and mitigate disease severity in a murine model of experimental autoimmune encephalomyelitis (EAE). Our approach toward Treg induction and maintenance represents a novel and translatable approach, as the hydrogels will be delivered by minimally invasive injection. Moreover, modularity of the material platform allows for facile bioconjugation of additional immunoregulatory signals as well as the co-delivery of antigen of choice. It therefore holds broad potential for treating autoimmune dysfunctions, organ rejection, and chronic inflammation after tissue injury.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $222,786 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	6/25/2026	NEW	$222,786
														Subtotal = $222,786

Grand Total All Awards = $222,786

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Injectable acellular hydrogels for local immunoregulation and tolerance

Award Number: R21AI199487

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/24/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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