CAREER: Determining and Tuning the Impact of Low-Level Metal-Based Nanoparticles on Actin Cytoskeleton in Normal and Cancer Cells

Nanomaterials may interact with human cells, due to the unintended release of nanomaterials into the environment (through air and water pollution), or intentionally in applications of nanomaterials for treating diseases such as cancer. Exposure of cells to nanomaterials can have dose-dependent beneficial or harmful effects. These effects are traditionally evaluated with biochemical assays such as cell viability and membrane integrity assays.

However, these approaches neglect the impact of nanomaterials on the cell’s actin cytoskeleton, the “bone structure” of the cells. This CAREER project will generate new knowledge about how low-level metal-based nanoparticles impact the actin cytoskeleton in normal and cancer cells. The potential impact of this project will be in offering a sensitive and quantitative platform based on actin cytoskeleton of cells for nanomaterial safety assessment, thus enabling the establishment of regulatory and manufacturing frameworks for safe and sustainable nanomaterials.

The project will also potentially lead to safe, effective, and versatile approaches for using nanomaterials to treat cancer metastasis (the cause of 90% of human cancer deaths). The research-integrated educational plan in this project places a strong emphasis on educating First-Generation College Students and Native American Students, two underrepresented groups in South Dakota currently exhibiting high dropout rates.

Through well-planned summer research experiences, a total of 10 students from these two groups are expected to acquire valuable hands-on skills in the fields of chemistry, biology, materials science, and nanobiotechnology, as well as enhanced academic persistence in completing their STEM education. The PI will also conduct a workshop series entitled “SEE NANO” at Tribal Colleges and integrate visually appealing and scientifically interesting research results with Flipped Classroom Methodology to make STEM classrooms more enjoyable and engaging, thereby promoting active learning and retention in STEM fields.

Most research on nanomaterial cytotoxicity relies on macroscopic biochemical assays, including cell viability and membrane integrity assays, without considering that nanoscale interactions with nanomaterials, even at low levels, can alter the actin cytoskeleton of cells. There is a knowledge gap concerning how the actin cytoskeleton of cells is affected by low concentrations of nanomaterials, when cell viability and membrane integrity have not been changed.

The overall research goal of this CAREER project is to determine how low-level metal-based nanoparticles affect the actin cytoskeleton in normal and cancer cells, and to apply this knowledge to tune their impact on the actin cytoskeleton for inhibition of cancer cell migration without impacting normal cells. The overarching hypothesis is that the interaction mechanism of metal-based nanoparticles with actin cytoskeleton will be dependent on their surface functionality and intracellular degradability, and these properties can be tuned to selectively disrupt the actin cytoskeleton in cancer cells without affecting the actin cytoskeleton in normal cells.

Specifically, this project will focus on two model metal-based nanoparticles including metal-organic frameworks and gold nanoparticles. Objective 1 will determine how low-level metal-based nanoparticles affect the actin structures and functions of vascular cells. Objective 2 will reveal the mechanisms of how these nanoparticles alter the actin structures and migration ability of cancer cells.

Finally, Objective 3 will predict and tune the impact of nanomaterials on the actin cytoskeleton in vascular and cancer cells by combining atomic force microscopy techniques with surface functionalization of nanoparticles. The actin cytoskeleton changes induced by the nanoparticles will be resolved by nanomechanical atomic force microscopy and super resolution fluorescence microscopy.

The mechanistic knowledge generated from this research will lead to: (i) a sensitive platform for nanoparticle safety assessment that is based on the biophysical responses of vascular cells; and (ii) several versatile, effective, and safe approaches for stopping cancer metastasis. The educational objective of this project is to improve the retention of undergraduates in STEM education, by engaging first-year students to specific research tasks focusing on nano-bio interactions, conducting a workshop series entitled “SEE NANO” at Tribal Colleges, and bringing Flipped Classroom Methodology to STEM classrooms.

The research integrated educational plan places a strong emphasis on educating First-Generation College Students and Native American Students, two underrepresented groups in South Dakota exhibiting high dropout rates after their first year. Engaging these students in research during their first summer will motivate and promote their academic persistence in completing STEM education.

The PI will also integrate visually appealing and scientifically interesting research results with Flipped Classroom Methodology to make STEM classrooms more enjoyable and engaging, thereby promoting active learning and retention in STEM fields.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.