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Continuous Probing of Nanoconstruct-Cell Interactions at Biologically Relevant Time Scales

Award Number: R01GM131421
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/27/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Continuous Probing of Nanoconstruct-Cell Interactions at Biologically Relevant Time Scales - PROJECT SUMMARY This renewal application builds on our discovery that the shape of nanoparticle-based constructs—what we define as structural valency—plays a key role in preserving the targeting ligand characteristics of nanoconstructs even when coated by a protein corona. Protein corona formation and its impact on engineered physicochemical properties of nanoconstructs has been somewhat controversial but is generally accepted to affect cell and tissue targeting specificity and downstream biological effects. Using single-particle, live-cell imaging investigations, we found that the protein corona composition of an ensemble of nanoconstructs was superseded by single-particle shape effects. Compared to their spherical counterparts, nanoconstructs with branched structures retained their ligand shell targeting capabilities both on cell membranes and within cells and cellular compartments. Statistically significant differences in the time-resolved dynamics of differently shaped nanoconstructs interacting with cellular components cannot be attributed to very minimal variations in protein corona composition. We aim to determine the mechanism for how branched nanoconstructs maintain their targeting functionality in biological environments and then to modulate the spatial organization of the single-particle protein corona with light during live-cell interactions. We will tune the nanoscale features of the branched nanoconstructs, including overall size, branch length, and tip radii of curvature, to be commensurate with membrane receptor dimerization and curvature-induced endosomal signaling and will image interactions at the single-particle level. The specific aims include (1) Understand how nanoconstruct design and optical stimuli can manipulate the protein corona at the single-particle level; (2) Investigate structural multivalency of membrane-targeting branched nanoconstructs on receptor dimerization; (3) Improve intracellular targeting and delivery using branched nanoconstruct shapes. This work is expected to be of high impact for precision nanomedicine by the intersection of single-nanoparticle advances with mechanistic insight into biological responses. Our ability to resolve nanoparticle-cell interactions at relevant time and length scales for receptor recognition and internalization will benefit knowledge in protein dimerization and nanoscale curvature effects and deepen understanding of endocytosis and immunomodulatory responses—key processes for advancements in vaccine design and drug delivery.


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: 2025 ( Subtotal = $302,563 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	7	8/19/2025	NON-COMPETING CONTINUATION	$302,563
														Subtotal = $302,563

Issue Date FY: 2024 ( Subtotal = $303,393 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	002	6	8/30/2024	NON-COMPETING CONTINUATION	$303,393
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	001	5	8/2/2024	COMPETING CONTINUATION	$2,412
2024	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	4	8/2/2024	NON-COMPETING CONTINUATION	-$2,412
														Subtotal = $303,393

Issue Date FY: 2023 ( Subtotal = $304,184 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	5	8/25/2023	COMPETING CONTINUATION	$304,184
														Subtotal = $304,184

Issue Date FY: 2022 ( Subtotal = $197,282 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	4	9/19/2022	NON-COMPETING CONTINUATION	$197,282
														Subtotal = $197,282

Issue Date FY: 2021 ( Subtotal = $197,807 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	3	8/26/2021	NON-COMPETING CONTINUATION	$197,807
														Subtotal = $197,807

Issue Date FY: 2020 ( Subtotal = $198,306 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	2	8/21/2020	NON-COMPETING CONTINUATION	$198,306
														Subtotal = $198,306

Issue Date FY: 2019 ( Subtotal = $267,708 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	1	9/19/2019	NEW	$267,708
														Subtotal = $267,708

Grand Total All Awards = $1,771,243

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Continuous Probing of Nanoconstruct-Cell Interactions at Biologically Relevant Time Scales

Award Number: R01GM131421

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/27/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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