Abstract 273: Cell Mimetic Liposomal Nanocarriers Tailored for Vascular Smooth Muscle Cell Molecular Therapeutics

Introduction: Our laboratory aims to develop biocompatible nanocarriers for molecular therapeutics aimed at vascular pathology. We have previously established a liposome platform that is an effective delivery system for RNAi in vascular smooth muscle cells (VSMC). Tailoring liposome membranes to mimic vascular cell membrane lipid constituents may be a promising strategy for increased delivery to target cells. Here we test our previously established liposome platform with the incorporation of naturally occurring signaling lipids known to influence vascular cell function as a method to increase VSMC association. Methods: Established cell-penetrating neutral liposomes (R8-PLPs) were assembled and fluorescently tagged as previously described. The propensity of diacylglycerol (DAG) and/or phosphatidylserine (PS) to increase the association of R8-PLP to VSMCs was tested by the incorporation of gradient percentages DAG/PS alone and in combination at 5-20% membrane occupancy. Liposome stability and siRNA encapsulate retention was analyzed via dynamic light scattering and Ribo-green, respectively. Results: DAG and PS incorporation increased VSMC association of R8-PLP, with 10% PS increased over all other groups (P10; Fig1A). Combinatorial formulations were screened for optimal DAG content with PS fixed at 10%. DAG20%+PS10% (D20P10) performed best, with increased VSMC association over all other combinatorial groups or independent P10 modification (Fig1B). Stability profiles were consistent (~50nm size and ~80% drug retention) and not significantly different among groups. Conclusion: Signaling lipid incorporation into the nanocarrier architecture potentiates VSMC association of established R8-PLP liposomes, without sacrificing stability or drug retention. These results suggest cell mimetic tuning of liposomes to generate specificity and increase delivery efficacy is a viable strategy for advancing targeted liposomal drug delivery.