Collaborative Research: Predictive Modeling of Coupled Nanoparticle-Membrane Mechanics as Determinants of Endocytic Pathways

This award supports a collaborative research project to understand how soft drug delivery particles enter cells. Nanoparticle-based therapies have strong potential to improve treatment for cancer, fibrosis, inflammation, and other diseases, but many promising particles fail because cells do not take them up efficiently or predictably. Most current design strategies focus on particle size, shape, charge, and surface chemistry. This project addresses a less understood but important factor: how the mechanical properties of a nanoparticle match the mechanical state of the target cell. The research will study soft, deformable nanogels that can interact with cell membranes in ways that more closely resemble natural biological particles such as viruses and extracellular vesicles. By explaining how particle softness and cell mechanics together control uptake, this project will provide new knowledge that can guide the design of safer and more effective drug delivery systems. The work advances biotechnology by supporting the development of mechanics-guided nanomedicine and contributes to national interests in health, prosperity, and scientific discovery. The project will also train graduate and undergraduate students in computational modeling, biomaterials, cell biology, and biomechanics, while supporting outreach activities that introduce high-school students to engineering and biomedical research. The project will establish a predictive framework for determining how nanogel deformability and cell mechanotype regulate cellular uptake pathways and intracellular routing. The central hypothesis is that nanogel stiffness, together with membrane tension, membrane bending rigidity, cytoskeletal coupling, and curvature-generating proteins, governs the efficiency, mechanism, and fate of nanogel internalization. The research integrates multiscale computational modeling with controlled experimental validation. Computationally, the project will combine coarse-grained models of deformable nanogels, ligand-receptor binding, and membrane mechanics with protein-enabled descriptions of clathrin, caveolae, and actin-associated membrane remodeling. Experimentally, mechanically tunable core-shell nanogels will be synthesized and characterized while controlling size, charge, and surface properties. Cellular uptake will be measured in lung epithelial and other relevant cell types with different mechanical properties using imaging, flow cytometry, pathway inhibition, and ultrastructural analysis. Together, these studies will define how nanogel mechanics affect uptake pathways, how target cell mechanics modulate uptake and trafficking, and how coupled particle-cell mechanical properties can be translated into general design rules. The expected outcome is a mechanics-based map that predicts when deformable nanocarriers will be efficiently internalized through specific pathways. This work will advance fundamental understanding in biomechanics and mechanobiology by linking material deformation, membrane remodeling, and biological transport at the cell surface. 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. NSF Award ID: 2607478 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Catherine Fromen | Institution: University of Delaware, NEWARK, DE | Award Amount: $279,964 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2607478 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2607478.html