Author ORCID Identifier

https://orcid.org/0000-0001-9274-3351

Date Available

1-1-2026

Year of Publication

2024

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Engineering

Department/School/Program

Biomedical Engineering

First Advisor

Dr. Sheng Tong

Second Advisor

Dr. Guigeng Zhang

Abstract

Cancer therapies that leverage reactive oxygen species (ROS) have shown potential for cancer inhibition due to their ability to induce oxidative stress in tumor cells. Iron oxide nanoparticles (IONPs) have garnered significant attention as a promising platform for ROS-dependent disease treatment, owing to their remarkable biocompatibility and Fenton catalytic activity. However, the low catalytic activity of IONPs has been a major hurdle in their clinical translation. To overcome this challenge, IONPs of different compositions are examined for their Fenton reaction under pharmacologically relevant conditions in this work. The results show that wüstite (Fe1-xO) nanoparticles exhibit higher catalytic activity than magnetite (Fe3O4) or maghemite (g-Fe2O3) of matched size and coating, despite having a similar surface oxidation state. Further analyses suggest that the high catalytic activity of wüstite nanoparticles can be attributed to the presence of internal low-valence iron (Fe0 and Fe2+), which accelerates the recycling of surface Fe3+ to Fe2+ through intraparticle electron transport. Additionally, ultrasmall wüstite nanoparticles are generated by tuning the thermodecomposition-based nanocrystal synthesis, resulting in a Fenton reaction rate 5.3 times higher than that of ferumoxytol, an FDA-approved IONP. Compared with ferumoxytol, wüstite nanoparticles substantially increase the level of intracellular ROS in mouse mammary carcinoma cells. This study presents a novel mechanism and pivotal improvement for the development of highly efficient ROS-inducing nanozymes, thereby expanding the horizons for their therapeutic applications.

In recent years, pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. H2O2 is then converted into cytotoxic hydroxyl free radicals (OH×) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to OH× by wüstite nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

These findings highlight a novel therapeutic strategy that combines highly efficient ROS generation with immune modulation. This dual approach not only enhances direct tumor cell killing but also activates the immune system, offering a promising advancement in cancer therapy.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.415

Funding Information

•NIH/NIBIB R01 (R01EB026893) •NIGMS/COBRE pilot grant (P20GM121327) •KY-INBRE grant (P20GM103436)

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Available for download on Thursday, January 01, 2026

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