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New Methods to Generate High-Performance Aptamers for in Vivo Monitoring of Small Molecules

Award Number: R01EB038048
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: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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New Methods to Generate High-Performance Aptamers for in Vivo Monitoring of Small Molecules - Summary. Aptamers – a versatile class of synthetic, nucleic-acid-based receptors – offer unique advantages for molecular sensing. Because of the hydrophilicity of oligonucleotides, for example, aptamers offer a key advantage relative to antibodies in terms of remaining soluble even when partially or fully unfolded. This distinctive characteristic renders it straightforward to engineer aptamers that fold and unfold in response to target binding and dissociation. In turn, this coupling of molecular recognition to a large-scale conformational change enables the construction of biosensors supporting real-time in vivo molecular measurements and chemo- responsive, materials whose properties change in response to a specific molecular cue. A major disadvantage of aptamers, however, is that their affinity and specificity are often insufficient for use under physiological conditions. Here, we present strong evidence that this poor performance is not an intrinsic limitation of nucleic acids, but instead arises from the limitations of conventional aptamer selection techniques. Building on this, we describe advanced aptamer selection and maturation approaches that we believe will surmount these limitations. In Aim 1, we propose the development of a powerful new aptamer selection approach, nuclease-assisted systematic evolution of ligands by exponential enrichment (NA-SELEX), which eliminates the need to attach either the target or the library to a solid support. This provides many important advantages over existing selection approaches, including the ability to simultaneously apply both thermodynamic and kinetic stringency and to easily carry out aptamer selection under physiologically relevant conditions, leading to enhanced in vivo aptamer performance. In Aim 2, we will complement NA-SELEX by developing an innovative “aptamer maturation” approach, Motif-SELEX, that can greatly improve the performance of underperforming first-generation aptamers. Motif-SELEX does this by providing new opportunities to explore the deep sequence space for a given aptamer during the selection process in order to optimize the geometry and complexity of that aptamer’s ligand-binding site, thereby increasing both its affinity and specificity. Finally, in Aim 3, we will showcase the improved performance and utility of the resulting aptamers by converting them into real-time biosensors to enable the currently unachievable feat of measuring a chemically diverse set of biomedically-important, low-concentration small-molecule targets in vivo. In the short term, the successful conclusion of our research program will yield sensors that enable clinically and scientifically useful real-time in vivo measurement of numerous biomedically- important low-molecular-weight analytes. The more far-reaching impact of this work will be the development of methods supporting the selection of aptamers with unprecedentedly high performance, greatly expanding the utility of these reagents for a wide range of biomedical applications.


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 = $691,316 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	5/26/2026	NEW	$691,316
														Subtotal = $691,316

Grand Total All Awards = $691,316

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New Methods to Generate High-Performance Aptamers for in Vivo Monitoring of Small Molecules

Award Number: R01EB038048

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: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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