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Magnetic Microrobots Assist AAV4 for CFTR Gene Delivery Through Mucus Barrier

Award Number: R21EB037346
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: 05/10/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Magnetic Microrobots Assist AAV4 for CFTR Gene Delivery Through Mucus Barrier - Scientific Abstract Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) anion channel. In CF patients, the loss of CFTR impairs airway host defense mechanisms, leading to chronic airway infections and inflammation, which are the primary causes of morbidity and mortality. It is generally believed that small airways are involved early in the pathogenesis of CF lung disease. Understanding the mechanisms underlying the pathogenesis is crucial for advancing CF therapy. Efficient and targeted delivery of CFTR cDNA to the small airway epithelium could correct the CFTR defect, restore host immune mechanisms, and prevent lung infections. Our research has demonstrated that the AAV4 serotype can transduce both large and small airway epithelial cells. However, delivering CFTR to small airways in CF animals and patients with advanced CF lung disease poses a significant challenge due to mucus and airway obstruction, as the viscoelastic mucus meshwork entraps and clears inhaled materials, efficiently removing them by mucociliary escalation. Our recent work on micro/nanorobotics, an emerging technique for active and targeted medicine delivery, indicated that microscale robots can be driven to penetrate biological fluids and tissues. We hypothesize that image-guided, magnetically triggered microrobots can facilitate AAV4-mediated CFTR gene delivery by penetrating the mucus obstruction. To achieve this, we propose three specific aims: Aim 1: Develop a micro-robotic AAV4 delivery system for CF airways. Aim 2: Test the hypothesis that the micro-robotic AAV4 delivery system-mediated transport of CFTR corrects airway surface liquid (ASL) properties and restores Cl- and HCO3- transport in small airway epithelia in CF patients in vitro. Aim 3: Conduct in vivo imaging and actuation of the micro-robotic AAV4 delivery system for CF treatment in a CF mouse model. This project will lead to completely new concepts in the field of CF gene therapy through direct mucus penetration and delivery. We built this project on the interdisciplinary expertise in microrobot-based therapy (Jinxing Li Lab) and CF biology and animal models (Xiaopeng Li Lab). If successful in our preclinical models, the new therapeutic strategy can be translated and transform the therapeutic landscape of CF to benefit patients. More broadly, the microrobot system can be further applied to other organs affected by CF, such as the gut and pancreas, where mucus barriers exist.


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 = $211,400 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 360	EAST LANSING	MI	48824	INGHAM	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	4/3/2026	NON-COMPETING CONTINUATION	$211,400
														Subtotal = $211,400

Issue Date FY: 2025 ( Subtotal = $235,500 )
2025	2025	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	5/7/2025	NEW	$235,500
														Subtotal = $235,500

Grand Total All Awards = $446,900

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Magnetic Microrobots Assist AAV4 for CFTR Gene Delivery Through Mucus Barrier

Award Number: R21EB037346

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: 05/10/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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