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Harnessing engineered drug-free polymeric nanoformulations to reprogram innate immune cells for spinal trauma

Award Number: R01NS136272
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/20/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Harnessing engineered drug-free polymeric nanoformulations to reprogram innate immune cells for spinal trauma - Project Summary/Abstract The endogenous tissue regeneration after traumatic spinal cord injury (SCI) is limited due to an inhibitory environment by secondary biological events including inflammatory responses. These events result in neural cell death and demyelination leading to various inflammation-mediated disorders. The long-term goal of this study is to develop effective acute intervention strategies that limit secondary injuries, thereby creating a permissive environment that supports regeneration. To achieve this goal, polymer based-nanoparticle (NP) formulations will be employed to reprogram the circulating innate cells in the blood after trauma. The scientific premise of the proposed research is based on preliminary data demonstrating that intravenously administered NPs target the pro-inflammatory sub-set of immune cells prior to extravasation to the injury and reprogram their trafficking patterns and phenotypes that limit inflammation and additional tissue damage, thereby inducing enhanced regeneration. Particularly, the immunomodulation is mediated by the physicochemical properties of NPs, indicating that NPs functions can be engineered differently to influence immune trafficking and phenotypes. The proposed engineered-NP formulations differentially reprogram innate cells, specifically immunomodulatory effects of NPs are sex-dependent and, importantly, these effects are solely mediated by distinctive physicochemical properties of NPs without the active biologics that can cause unfavorable off-target effects. In this proposal, key physicochemical parameters of NP formulations will be identified for effective immunomodulation in males and females respectively since the differences in physiological factors between sexes play a critical role in inflammation after spinal trauma. Aim 1 will focus on interactions between different NP formulations and innate cells in circulation to identify more effective NP design factors that limit inflammation in both sexes. Distinct physicochemical properties of NPs will differently affect innate cells trafficking and phenotype, which will be sex-dependent and subsequently, reprogram an inhibitory environment. NP-induced differential cellular internalization, phenotype, activation, pharmacokinetic profiles as well as biodistribution of NPs will be investigated. Aim 2 will investigate the long-term impacts of NPs on anatomical and functional regeneration after SCI with a more focused set of NP formulations based on Aim 1. Initially, NP-associated immune cells will be investigated, then the extent of axonal regrowth and remyelination, synaptogenesis, and functional recovery in the chronic phase of SCI will be assessed. Collectively, the proposed studies will have the potential to be a transformational therapy by identifying the relationship between physicochemical parameters and immune modulation for effective NP formulations to support regeneration. Notably, NPs are made of FDAapproved polymeric biomaterial enabling them to be readily stored for immediate administration non-invasively as a means to modulate the innate immune system for functional enhancement.


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 = $326,594 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/3/2026	NON-COMPETING CONTINUATION	$326,594
														Subtotal = $326,594

Issue Date FY: 2025 ( Subtotal = $293,936 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/20/2025	NON-COMPETING CONTINUATION	$293,936
														Subtotal = $293,936

Issue Date FY: 2024 ( Subtotal = $326,594 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/20/2024	NEW	$326,594
														Subtotal = $326,594

Grand Total All Awards = $947,124

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Harnessing engineered drug-free polymeric nanoformulations to reprogram innate immune cells for spinal trauma

Award Number: R01NS136272

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/20/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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