Development of Cell-Derived Plasma Membrane Vesicles as a Nanoparticle Encapsulation and Delivery System.

Purpose: Developing non-invasive delivery platforms with a high level of structural and/or functional similarity to biological membranes is highly desirable to reduce toxicity and improve targeting capacity of nanoparticles. Numerous studies have investigated the impacts of physicochemical properties of engineered biomimetic nanoparticles on their interaction with cells, yet technical difficulties have led to the search for better biomimetics. To overcome such challenges, we aimed to develop a novel method using cell-derived giant plasma membrane vesicles (GPMVs) to encapsulate a variety of engineered nanoparticles, then use these core-shell, nanoparticle-GPMV vesicle structures to deliver cargo to other cells. Methods: GPMVs were generated by chemically inducing vesiculation in A549 cells, a model human alveolar epithelial line. To evaluate the ability of GPMVs to encapsulate intracellular content, plain, carboxy-modified, or amine-modified silica nanoparticles (all, ~ 50 nm diameter) were loaded into the parent cells prior to vesiculation. GPMVs with or without nanoparticles were subsequently evaluated for stability, membrane protein and lipid constituents, and uptake into cells, and compared to relevant controls. Results: Cell-derived GPMVs retained encapsulated silica nanoparticles for at least 48 hours at 37 °C. GPMVs showed nearly identical lipid and protein membrane profiles as the parental cell plasma membrane, with or without encapsulation of nanoparticles. Notably, GPMVs were readily endocytosed in the parental A549 cell line as well as the human monocytic THP-1 cell line. Higher cellular uptake levels were observed for GPMV-encapsulated nanoparticles compared to control groups, including free nanoparticles. Further, GPMVs delivered a variety of nanoparticles to parental cells with reduced cytotoxicity compared to free nanoparticles at concentrations that were otherwise significantly toxic. Conclusions: We have introduced a novel technique to load nanoparticles within the cell plasma membrane during the GPMV vesiculation process. These GPMVs are capable of (a) encapsulating different types of nanoparticles (including larger and not highly-positively charged bodies that have been technically challenging cargoes) using a parental cell uptake technique, and (b) improving delivery of nanoparticles to cells without significant cytotoxicity. Ultimately, the use of GPMVs or other complex vesicles with endogenous cell surface membrane proteins and lipids can lead to highly effective cell membrane-based nanoparticle/drug delivery systems.