Fusion-Inducing Liposomes for Efficient Intracellular Delivery: Continuum Models and Experiments

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Bringing mathematical and computational scientists together with biomedical engineers, this project addresses an unmet and growing need for a simple, safe, and efficient system to deliver macromolecules to the cellular interior. Therapeutic macromolecules, for example, peptides and proteins, have tremendous potential in medical fields but their clinical applications have remained limited as their delivery is much more challenging compared to small molecule therapeutics. A promising family of carriers, called fusogenic liposomes, suffer from a key shotcoming: the high concentrations of fusogenic lipids needed to cross cellular membrane barriers lead to toxicity in vivo. This limitation may be overcome by creating liposomes that contain relatively low concentrations of fusogenic lipids but can present them in dense patches on their surfaces. This may be achieved through membrane phase-separation, a mechanism that biological membranes often use to locally concentrate specific lipid species. This project will apply complementary mathematical, computational, and experimental tools to (i) design and develop a new class of liposomal carriers, called patchy fusogenic liposomes (PFLs), and (ii) investigate how the fusogenic patches affect the ability of PFLs to fuse with cellular membranes. Broader impacts include training opportunities for participating students. Undergraduate and graduate students will be trained to work at the interface of experimental bioengineering, applied mathematics, and scientific computing. Cross-disciplinary conversations will be fostered by close interactions and joint meetings.The use of massive numerical experimentation to support and complement experimental practice in the design of liposomes requires highly efficient and computationally cheap numerical methods. Despite recent advances, molecular dynamics and coarse grain models still feature high computational costs. This project will focus on sophisticated novel continuum models and combine them with numerical algorithms and data analysis tools to produce a highly efficient computational platform. The multiphysics model under consideration accounts for lateral phase-separation, membrane fluidity, and electrostatic interaction and its predictive capability will be assessed against experimental data through a multi-stage validation process. High computational efficiency in implementing the model will be achieved through physics-based and directional splitting algorithms for a robust geometrically unfitted finite element method. Once validated, the software will be systematically deployed to investigate the role of critical PFL characteristics for membrane fusion. Ultimately, this project will deliver the design of PFLs that feature minimal amounts of fusogenic components while maximizing the chances of fusion with other membranes. The efficient computational methods for surface PDEs and coupled surface-bulk systems developed for this project could be used for a large variety of applications, from simulations of tumor growth to modeling of eukaryotic cell motility. In addition, the newly developed software will be open source.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.