(700d) The Role of Membrane-Particle Interactions in Polymer-Based Gene Delivery Systems

Human gene therapy shows broad potential as a primary means of treating disease. Polymer-based vectors rely on the ability to electrostatically bind and condense the genetic material into nanoparticles, which are termed polyplexes. Designing an efficient gene-delivery vector requires a mechanistic understanding of each step during the gene delivery process. In this work, we focus on the escape from enzymatic degradation within the endosome via the proton sponge mechanism. We employ a self-consistent field theory (SCFT) to study the thermodynamics of membrane-particle interactions, specifically focusing on the role of the electrostatics in the system. We find that the particles where a metastable hydrophilic pore state can exist are the same particles which cause membrane permeability and hole formation in experimental observations. Our results also indicate that the pore significantly lowers the critical tension necessary for membrane rupture, thus enhancing the release of the trapped genetic material from the endosome. Interestingly, we find that multiple solutions (e.g., a highly deformed membrane wrapping a particle or a hydrophilic membrane pore with an inserted particle) can exist for the same particle and membrane tension. This points to multiple kinetic pathways, which require minimum energy path calculations to reveal the structure of the membrane en route to the formation of a pore, and the energies associated with the rearrangement of the lipids and the insertion of the particle in these high energy transition states.