Wednesday, December 31, 2025 12/31/2025

Programmable 'all-in-one' RNA as a molecular scaffold for targeted combinatorial innate immune activation

Award Number: R21EB035261
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Programmable 'all-in-one' RNA as a molecular scaffold for targeted combinatorial innate immune activation - PROJECT SUMMARY: The generation of a robust disease-specific immune response is a critical challenge in cancer immunotherapies, many of which provide clinical benefit in only a fraction of patients despite remarkable successes, and in infectious disease vaccines. Harnessing the innate immune system, which has evolved to sense and respond to complex combinations of pathogen-associated molecular patterns, is highly promising for augmenting cancer immunotherapies and infectious disease vaccines. While many synthetic innate immune agonists that activate pattern recognition receptors (PRRs) have been developed as vaccine adjuvants, only a handful of adjuvants have been clinically approved. Generation of a durable immune response faces key barriers: (1) many current PRR agonist-based adjuvants rely on a single agonist, poorly recapitulating natural pathogen recognition by the innate immune system; (2) while mounting evidence shows that combining PRR agonists can promote synergistic activation, control and understanding of the combinatorial effects and spatial modulation of multiple agonists remain inadequate; and (3) further exacerbating these gaps is a scarcity of platforms for precisely tuning combinations and spatial arrangements of innate immune agonists. To address these knowledge and technological gaps, the proposed work will engineer a molecularly defined, modular “all-in-one” platform that utilizes RNA as both a multifunctional agonist and scaffold to sculpt the immune response via (1) precise spatial patterning and multivalency of PRR agonists; (2) combinatorial control of innate immune signaling pathways; and (3) targeted self-delivery. The first aim will leverage the programmable structural features and sequence of a modular RNA scaffold to combine and pattern PRR agonists for synergistic innate immune activation. In an orthogonal aim, the team will exploit the natural immune cell-targeting abilities of fungal wall polysaccharides to create a bioinspired, “all-in-one” synthetic glyco-RNA that can target and activate antigen-presenting cells. The translational potential of the developed RNA platform will then be explored in a proof-of-concept evaluation of in vivo therapeutic efficacy in the third aim, using a syngeneic mouse model of melanoma. If successful, the proposed work will introduce a new paradigm for the rational design of combinatorial innate immune agonists and a new class of synthetic glyco-RNA therapeutic molecules for targeted immune activation. The highly modular platform will enable (1) fundamental studies of how combinations of innate immune agonists and their spatial arrangements function at the molecular, cellular, and organismal levels; and (2) precise modulation of disease-specific immune responses for applications in cancer and infectious diseases.


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 = $179,450 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	12/16/2025	NON-COMPETING CONTINUATION	$179,450
														Subtotal = $179,450

Issue Date FY: 2025 ( Subtotal = $186,537 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	2	5/19/2025	NON-COMPETING CONTINUATION	$18,654
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	11/19/2024	NON-COMPETING CONTINUATION	$167,883
														Subtotal = $186,537

Issue Date FY: 2024 ( Subtotal = $186,865 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	1/1/2024	NEW	$168,179
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	1	6/14/2024	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	1	4/25/2024	NEW	$18,686
														Subtotal = $186,865

Grand Total All Awards = $552,852

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Programmable 'all-in-one' RNA as a molecular scaffold for targeted combinatorial innate immune activation

Award Number: R21EB035261

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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