CAREER: Effects of Nanomaterial Chirality on Immune Cells and Innate Immunity

Chirality, or handedness, is a property of an object which is not superimposable with its mirror image. It is manifest at scales ranging from molecules to galaxies and has fascinated scientists as well as artists, and mathematicians for centuries. Biomolecules like proteins and sugars uniquely exhibit one handedness in all living systems, and chirality also permeates at the supramolecular level, for example, in DNA, microtubules, and actin filaments.

An emerging area of nanomaterials research is to extend chirality from molecules to materials where naturally left-handed amino acids are exchanged for their right-handed chiral counterparts. Cells can sense and respond to the chirality of nanomaterials in their immediate environment, and cellular interactions ultimately determine nanomaterial effectiveness and safety.

Through this CAREER project, the investigator will utilize natural and chiral versions of self-assembling peptides to investigate how the chiral properties of nanomaterials affect their interaction with cells of the immune system and their subsequent intracellular fate. Such studies will further our understanding of how chirality effects emerge from a molecular level to the bulk level and permit the fabrication of right-handed nanomaterials for a broad range of applications in biotechnology.

Knowledge of chiral peptide assembly and their interactions with immune cells will inform the design and development of cell-free and synthetic nanomaterial vaccines against infectious and non-infectious diseases with better safety profiles. This project also supports integrated education and outreach activities where the investigator will develop data science-rich learning modules to introduce concepts of chiral structures and nanoengineering in classical undergraduate engineering courses.

The project will also create educational workshops for K-12 teachers which are focused on interactive software modules to transition chirality concepts to the classroom. The investigator will also engage community participation through outreach events to take place at the St. Louis Science Center and Academy of Science.

This CAREER award supports a transformative research and education project to understand how sentinel immune cells like macrophages and dendritic cells which have evolved to protect us from both external and internal threats, interact and process chiral peptide-based nanomaterials. Understanding the uptake and subsequent intracellular fate of chiral peptide nanomaterials by the immune system is of fundamental relevance for the continued development and use in biomedical and environmental applications.

To advance this knowledge, this project will use natural and chiral variants of peptide building blocks which spontaneously self-organize into supramolecular three-dimensional nanomaterials. Chiral versions are subtle in that they do not change side-chain size, flexibility, hydropathy, charge, or polarity and allow focus to be placed solely on the question of how changes in amino acid side-chain orientation and the resultant alterations in peptide backbone structure affect cellular interactions with nanomaterials.

The objectives of this project are to: (1) characterize mechanisms of cellular uptake for different chiral compositions using physicochemical and pharmacological interventions; (2) determine cellular clearance and activation of innate immune pathways; and (3) assess effects on antigen presentation and adaptive immune responses. These studies will provide new insight into interactions that will impact our understanding of chirality and inform nanomaterial design to lay a foundation for lasting scientific contributions in the areas of chiral biohybrid nanomaterials incorporating peptides and inorganics, discovery of previously unknown scavenger receptors, combining cellular data with modeling towards predictive nanomaterial fabrication, and testing the role of nanomaterials in actively engaging cellular processes.

Closely tied to the research project are educational and outreach events that will help the PI implement a multi-tiered, student, teacher, and community-centered mentorship targeted at growing the infrastructure of engineers with a strong background in nanomaterials research. Collaborative efforts with the Saint Louis Science Center and Saint Louis Academy of Sciences signature youth development project will help train teens who are socio-economically disadvantaged and underrepresented minorities to set and achieve educational and STEM-related career goals.

The Science Center is also a member of the Portal to the Public Network that actively works to connect public audiences with the scientists working in their communities.

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.