Unraveling the Biological Effects of Engineered Nanomaterials from a Mitochondrial Perspective

/Abstract Despite their widespread presence in our modern life, the biological effects of engineered nanomaterials (ENMs) under exposure conditions that more accurately reflect real-world human experiences (low doses over extended periods) remain poorly understood. Our preliminary data using primary human dermal fibroblasts demonstrate that gold nanoparticles (AuNPs), one of the most promising ENMs for biomedical applications, modulate key mitochondrial-health parameters at the molecular, cellular, and functional levels following chronic, low-dose ex- posure. These effects are closely associated with the specific physicochemical properties of the AuNPs used. Mitochondria are central to cellular homeostasis, and mitochondria dysfunction is associated with the develop- ment and progression of chronic diseases. Building on our preliminary findings, we hypothesize that ENMs, even at low, subtoxic concentrations, modulate mitochondrial health through distinct mechanisms that vary based on their physicochemical characteristics in the long term. Depending on the nanoparticle properties and cellular context, both harmful and beneficial outcomes may occur. To test this hypothesis, we will systematically char- acterize the acute and chronic effects of well-defined AuNPs on mitochondrial health using low-dose exposures in relevant in vitro approches, including healthy and disease models associated with mitochondrial dysfunction. By integrating molecular, cellular, and functional analyses, this research will advance our understanding of how ENMs influence mitochondrial function under realistic exposure scenarios. The proposed work will provide foun- dational insights linking ENM properties to biological outcomes, supporting the design of safer nanotechnologies and informing future therapeutic strategies. This project will also provide meaningful research opportunities for undergraduate students, building research capacity at Auburn University in alignment with the goals of the NIH R15 AREA program. Project Number: 1R15ES038685-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Priscila Falagan Lotsch | Institution: AUBURN UNIVERSITY AT AUBURN, Auburn, AL | Award Amount: $571,566 | Activity Code: R15 | Study Section: Special Emphasis Panel[ZRG1 BBBT-T (87)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11361354