Award Abstract # 1752197
CAREER: Revealing the fundamental interactions of cell-penetrating nanoparticles in a complex model membrane

NSF Org: CBET
Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient: UNIVERSITY OF TENNESSEE
Initial Amendment Date: December 15, 2017
Latest Amendment Date: December 15, 2017
Award Number: 1752197
Award Instrument: Standard Grant
Program Manager: Nora Savage
nosavage@nsf.gov
 (703)292-7949
CBET
 Division of Chemical, Bioengineering, Environmental, and Transport Systems
ENG
 Directorate for Engineering
Start Date: September 1, 2018
End Date: September 30, 2024 (Estimated)
Total Intended Award Amount: $540,093.00
Total Awarded Amount to Date: $540,093.00
Funds Obligated to Date: FY 2018 = $540,093.00
History of Investigator:
  • Stephen Sarles (Principal Investigator)
    ssarles@utk.edu
Recipient Sponsored Research Office: University of Tennessee Knoxville
201 ANDY HOLT TOWER
KNOXVILLE
TN  US  37996-0001
(865)974-3466
Sponsor Congressional District: 02
Primary Place of Performance: University of Tennessee Knoxville
TN  US  37996-0003
Primary Place of Performance
Congressional District:
02
Unique Entity Identifier (UEI): FN2YCS2YAUW3
Parent UEI: LXG4F9K8YZK5
NSF Program(s): Nanoscale Interactions Program
Primary Program Source: 01001819DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1045, 7237
Program Element Code(s): 117900
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

This CAREER award supports a transformative research and education program to understand how novel types of nano-scale particles penetrate cellular membranes in a passive and seemingly nondestructive manner. Revealing these details will unlock tremendous potential for developing useful cell penetrating agents in biomedicine and agriculture and enable us to better discern the safety of nanomaterials. To lay a foundation for lasting scientific contributions, the research project will leverage new methods pioneered by the Principal Investigator to assemble and characterize complex model membranes that better mimic those found in cells. This research will generate new knowledge of how the chemistry and patterning of nanoparticle surfaces enable their uptake in cells, which will directly benefit the design, testing, and use of new generations of nanomaterials. Closely tied to the research project, an educational and outreach program entitled INTERFACE will enable a wider range of people to engage in and interact with the research and technologies produced in the PI's lab as a result of this project. INTERFACE includes public forums on the nature and context of bio-active nanoparticles, hands-on research activities for K-12 and undergraduate students, and support for STEM-focused journalism and improved science communication activities. These activities support broader impacts by generating interest in STEM, educating the public, improving scientific journalism, increasing participation of underrepresented groups, and enriching engineering curricula.

This CAREER award supports a transformative research and education program to understand how novel types of amphiphilic monolayer-protected nanoparticles passively, and seemingly nondestructively, penetrate cellular membranes. Revealing these mechanisms will unlock tremendous potential for cell penetrating agents in biomedicine and enable us to better discern the safety of nanomaterials. To lay a foundation for lasting contributions, the proposed project will leverage new methods pioneered by the PI to assemble complex lipid bilayers that better mimic membranes in cells and characterize in situ both their structural and transport properties. The research project seeks to: 1) develop transformative tools for manipulating, characterizing, and imaging complex model membranes; 2) quantify the effects of amphiphilic nanoparticle adsorption, insertion, and translocation on membrane structure; 3) uncover the effects of lipid type and thermotropic phase on nanoparticle activity; and 4) examine converse effects of nanoparticles on lateral organization in membranes. The intellectual merit stems from the stated objectives and expected outcomes to clearly understand how amphiphilic nanoparticles penetrate membranes by linking their activities to membrane capacitance, thickness, tension, intra-membrane potential, conductance, and lateral organization of peptides. By studying homogeneous and heterogeneous membranes that can be assembled to mimic a variety of cells, this work will generate new information about which lipid domains are preferred and test hypotheses that amphiphilic nanoparticles prefer defects, areas of higher curvature, and cholesterol-lean regions. Closely tied to the research, an educational and outreach program entitled INTERFACE will enable a wider range of people to engage in and interact with the research and technologies produced in the Principal Investigator's lab as a result of this project. INTERFACE includes public forums on the nature and context of bioactive nanoparticles, hands-on research activities for K-12 and undergraduate students, and support for STEM-focused journalism and improved science communication activities.

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.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Basham, Colin M. and Premadasa, Uvinduni I. and Ma, Ying-Zhong and Stellacci, Francesco and Doughty, Benjamin and Sarles, Stephen A. "Nanoparticle-Induced Disorder at Complex LiquidLiquid Interfaces: Effects of Curvature and Compositional Synergy on Functional Surfaces" ACS Nano , v.15 , 2021 https://doi.org/10.1021/acsnano.1c02663 Citation Details
Basham, Colin M. and Spittle, Stephanie and Sangoro, Joshua and El-Beyrouthy, Joyce and Freeman, Eric and Sarles, Stephen A. "Entrapment and Voltage-Driven Reorganization of Hydrophobic Nanoparticles in Planar Phospholipid Bilayers" ACS Applied Materials & Interfaces , v.14 , 2022 https://doi.org/10.1021/acsami.2c16677 Citation Details
Koner, Subhadeep and Tawfik, Joseph and Mashali, Farzin and Kennison, Kristen B. and McClintic, William T. and Heberle, Frederick A. and Tu, Yu-Ming and Kumar, Manish and Sarles, Stephen A. "Homogeneous hybrid droplet interface bilayers assembled from binary mixtures of DPhPC phospholipids and PB-b-PEO diblock copolymers" Biochimica et Biophysica Acta (BBA) - Biomembranes , v.1864 , 2022 https://doi.org/10.1016/j.bbamem.2022.183997 Citation Details
Mashali, Farzin and Basham, Colin M and Xu, Xufeng and Servidio, Camilla and Silva, Paulo_H Jacob and Stellacci, Francesco and Sarles, Stephen A "Simultaneous Electrophysiology and Imaging Reveal Changes in Lipid Membrane Thickness and Tension upon Uptake of Amphiphilic Gold Nanoparticles" Langmuir , v.39 , 2023 https://doi.org/10.1021/acs.langmuir.3c01973 Citation Details
Ringley, Jessie D. and Sarles, Stephen Andrew "Temperature-Controlled Assembly and Characterization of a Droplet Interface Bilayer" Journal of Visualized Experiments , 2021 https://doi.org/10.3791/62362 Citation Details

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

The long-term, 5-year goal of this CAREER project at the University of Tennessee Knoxville (UTK) is to uncover the physical interactions that occur passively, and seemingly nondestructively, between a novel class of cell penetrating nanoparticles (NPs) and cellular membranes. Revealing these mechanisms in model lipid membranes that better mimic those found in cells will transform the design, testing, and use of cell penetrating NPs across biomedicine and enable us to better discern the safety of nanomaterials. However, our current understanding of NP interactions with membranes is limited by our ability to measure their effects, which occur at very small length scales. The PI and students thus worked to achieve these goals through an integrated research and education program that combined experiments on model lipid membranes, developing new experimental methods and training students in these methods, and disseminating the findings of our work throughout the local community. Successful outcomes of this research include: 1) new understanding of the spontaneous interactions between lipids and NPs, including how NPs affect the molecular scale orientations of lipids; 2) new measurement methods to precisely incorporate and assess the effects of NPs on membrane physical properties; 3) new understanding on how the hydrophobicity of the particle and the lipid type affects its spontaneous incorporation and membrane alteration; and 4) new recipes for model membrane formation. These findings resulted in multiple peer-reviewed publications led by student researchers and multiple conference presentations given by students. This grant also had broader impacts on professional development and education that benefited multiple groups. The grant directly supported 2 PhD students doing research in the PI’s lab. One PhD student graduated in 2023 and the second will graduate in 2025. The first student is now working as a postdoctoral researcher in the Carolina Cancer Nanotechnology T32 Training Program at the Univ. of North Carolina at Chapel Hill. This CAREER project provided opportunities to train undergraduate researchers, including two who are now graduate students at other universities. The project also provided scientific context with which to educate visiting high school students during each of the 5 years of the project, engage undergraduate Journalism students in an Environmental and Science writing course taught at UTK, and disseminate the goals, methods, and findings of the project to the general public through the UT Science Forum in Knoxville, TN.

 


Last Modified: 02/11/2025
Modified by: Stephen A Sarles

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