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Engineered Synthetic Low-Density Lipoprotein Nanoparticles for Enhanced Cancer Immunotherapy in Head and Neck Cancer

Award Number: R01DE035487
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Engineered Synthetic Low-Density Lipoprotein Nanoparticles for Enhanced Cancer Immunotherapy in Head and Neck Cancer - Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Despite technological advancements, the 5-year survival rate for advanced HNSCC has remained stagnant for the past three decades. The FDA has approved immune checkpoint inhibitors (ICIs), including pembrolizumab and nivolumab, for the treatment of recurrent and metastatic HNSCC. While immunotherapy can induce durable remissions, only 15–20% of patients respond to treatment. There is growing interest in combining ICIs with chemotherapy or radiotherapy to enhance therapeutic efficacy. However, this approach has faced significant setbacks in recent clinical trials. Emerging studies suggest that the lack of activated dendritic cells (DCs) in tumors is a major reason for immunotherapy failure. Therefore, developing therapeutic strategies that not only eliminate cancer cells but also release stimulatory factors to promote intratumoral DC maturation and migration holds great promise for enhancing tumor sensitivity to immunotherapy. Our goal is to develop a novel adjuvant nanotechnology based on 7-dehydrocholesterol (7DHC)- encapsulated synthetic low-density lipoproteins (7DHC-LDLs) to boost anti-tumor immunity when used in combination with ICIs. 7DHC, a cholesterol analog, exhibits the highest rate of free radical chain propagation among known lipid molecules. Our preliminary data demonstrate that 7DHC-LDLs, like natural LDLs, accumulate in tumors by binding to the LDL receptor, which is upregulated in HNSCC. In the presence of reactive oxygen species (ROS), 7DHC triggers and amplifies lipid peroxidation in cell membranes, leading to ferroptotic cell death. In addition, our data suggest that cancer cells killed by 7DHC release danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines, which activate DCs and enhance tumor-reactive T cell priming, even in immunologically “cold” tumors. In this project, we will evaluate the pharmacokinetics and biodistribution of 7DHC-LDLs in orthotopic HNSCC models. We will test whether the innate adjuvant effects of 7DHC-LDLs can be leveraged to enhance the efficacy of anti-PD-L1 checkpoint blockade. Finally, we will perform a comprehensive analysis of the tumor microenvironment to elucidate the impact of this combination therapy.


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 = $644,452 )
2026	2026	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Oral Diseases and Disorders Research	000	1	2/18/2026	NEW	$644,452
														Subtotal = $644,452

Grand Total All Awards = $644,452

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Engineered Synthetic Low-Density Lipoprotein Nanoparticles for Enhanced Cancer Immunotherapy in Head and Neck Cancer

Award Number: R01DE035487

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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