Modulating and Modeling the Surface ζ Potential of Hybrid Lipid/Polymer Nanovesicles: Implications for Surface Modification and Drug Delivery

Hybrid lipid/polymer membranes offer superior tunability over lipid-only systems, for a wide range of potential applications in surface modification and drug delivery, including nanovesicles (NVs) for mRNA-based therapeutics. The polymeric component can be readily modified for specific properties, and the lipid-to-polymer composition can be adjusted for even finer control. However, these materials are still an emerging field of study, and their potential is not yet fully understood. Modulating and modeling the ζ potential of these membranes is a critical step toward controlling their surface interactions. In this study, we performed ζ potential analysis on NVs with diameters of ∼100 nm made from lipids (1,2-dioleoyl-3-trimethylammonium propane, 1,2-dioleoyl-sn-glycero-3-phospho-l-serine, and 1,2-dioleoyl-sn-glycero-3-phosphocholine) and amphiphilic block copolymers (PEO–PBd, PBd–PEO–NH3+, and PBd–PEO–COO–) at various compositions. This study revealed that NVs composed of the polymer PEO–PBd are surprisingly resilient to attempts to change their ζ potential with the addition of anionic or cationic lipids, which could limit their utility for drug-delivery applications and strategies to modify their surface chemistry. To overcome these limitations and explain these results, we devised a simple predictive and explanatory model that allows estimation of the ζ potential of hybrid NVs containing charged lipids. Our results indicate that the location of the charged groups can be controlled in order to impact the visibility of those charged groups to the surrounding materials and tissues that synthetic NVs interact with. We anticipate that our approach will greatly facilitate the design and modulation of the ζ potential and other properties of polymer NVs and other biomimetic membrane materials for nanomedicine and nanobiosensors.