Glutamine-Functionalized mRNA Lipid Nanoparticles Block HIF-1α-Dependent Glycolytic Adaptation to Sensitize Azelaic Acid Therapy in Colorectal Cancer
- 1Department of Gastrointestinal Surgery, Minhang Hospital, Fudan University, Shanghai 201199, China
- 2Department of General Surgery, People’s Hospital of Daguan County, Zhaotong 657400, China
- 3Department of Pathology, Minhang Hospital, Fudan University, Shanghai 201199, China
Abstract
Metabolic plasticity limits mitochondria-directed cancer therapy by enabling glycolytic compensation during respiratory stress. Our previous nano-energy interference (NEI) platform showed that coupling azelaic acid (AZA)-induced mitochondrial disruption with restriction of glucose utilization suppresses colorectal cancer (CRC), but the upstream program coordinating this adaptive response remained unresolved. Here, we identify HIF-1α-dependent glycolytic adaptation as a key response to AZA-induced respiratory inhibition and develop glutamine-functionalized lipid nanoparticles (G-LNPs) to deliver dominant-negative HIF-1α (dnHIF-1α) mRNA. G-LNPs were approximately 105 nm in diameter, achieved >90% mRNA encapsulation, and enhanced uptake and functional reporter mRNA expression in ASCT2-expressing MC38 cells in a GPNA-sensitive manner. AZA suppressed mitochondrial respiration while activating HIF-responsive transcription, glycolytic activity, lactate production, and GLUT1, HK2, LDHA, and PDK1 expressions. G-LNP-delivered dnHIF-1α blocked this compensatory response without materially intensifying respiratory inhibition, thereby deepening ATP depletion and producing a distinct treatment-associated metabolomic state. Following treatment withdrawal and equal viable cell replating, the combination caused persistent impairment of regrowth and clonogenic capacity. In subcutaneous MC38 tumors, combined treatment produced the greatest tumor growth inhibition without overt systemic toxicity. Together, these findings support transient disruption of HIF-dependent metabolic adaptation as a strategy to convert partially recoverable mitochondrial stress into a durable loss of CRC cell fitness.
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BibTeX
@article{teng2026glutaminefunctionalized,
title = {{Glutamine-Functionalized mRNA Lipid Nanoparticles Block HIF-1α-Dependent Glycolytic Adaptation to Sensitize Azelaic Acid Therapy in Colorectal Cancer}},
author = {Fei Teng and Yuanyuan Yang and An Xiong and Rongjian Zhou and Chencheng Shi and Chang Su and Xiaodong Shen and Mengxuan Yang and Ming Lei and Yiou Cao and Yi Chen and Puhua Wang and Shaoqun Liu},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31213791},
url = {https://www.mdpi.com/1420-3049/31/21/3791},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Glutamine-Functionalized mRNA Lipid Nanoparticles Block HIF-1α-Dependent Glycolytic Adaptation to Sensitize Azelaic Acid Therapy in Colorectal Cancer
AU - Fei Teng
AU - Yuanyuan Yang
AU - An Xiong
AU - Rongjian Zhou
AU - Chencheng Shi
AU - Chang Su
AU - Xiaodong Shen
AU - Mengxuan Yang
AU - Ming Lei
AU - Yiou Cao
AU - Yi Chen
AU - Puhua Wang
AU - Shaoqun Liu
PY - 2026
DA - 2026/10/22
JO - Molecules
DO - 10.3390/molecules31213791
UR - https://www.mdpi.com/1420-3049/31/21/3791
AB - Metabolic plasticity limits mitochondria-directed cancer therapy by enabling glycolytic compensation during respiratory stress. Our previous nano-energy interference (NEI) platform showed that coupling azelaic acid (AZA)-induced mitochondrial disruption with restriction of glucose utilization suppresses colorectal cancer (CRC), but the upstream program coordinating this adaptive response remained unresolved. Here, we identify HIF-1α-dependent glycolytic adaptation as a key response to AZA-induced respiratory inhibition and develop glutamine-functionalized lipid nanoparticles (G-LNPs) to deliver dominant-negative HIF-1α (dnHIF-1α) mRNA. G-LNPs were approximately 105 nm in diameter, achieved >90% mRNA encapsulation, and enhanced uptake and functional reporter mRNA expression in ASCT2-expressing MC38 cells in a GPNA-sensitive manner. AZA suppressed mitochondrial respiration while activating HIF-responsive transcription, glycolytic activity, lactate production, and GLUT1, HK2, LDHA, and PDK1 expressions. G-LNP-delivered dnHIF-1α blocked this compensatory response without materially intensifying respiratory inhibition, thereby deepening ATP depletion and producing a distinct treatment-associated metabolomic state. Following treatment withdrawal and equal viable cell replating, the combination caused persistent impairment of regrowth and clonogenic capacity. In subcutaneous MC38 tumors, combined treatment produced the greatest tumor growth inhibition without overt systemic toxicity. Together, these findings support transient disruption of HIF-dependent metabolic adaptation as a strategy to convert partially recoverable mitochondrial stress into a durable loss of CRC cell fitness.
SN - 1420-3049
ER -