| Summary: | Lipid nanoparticles, including liposomes, have emerged as promising vehicles for the delivery of a variety of therapeutics. Several formulations have been approved and are used in medical practice—the COVID-19 mRNA vaccines represent the most recent milestone. Achieving effective oral delivery would elevate the potential of these formulations. Therefore, this study investigates the oral application of mRNA using liposomes as a nanocarrier system. A cyclic cell-penetrating peptide was coupled to the liposomal surface to allow uptake into the intestinal mucosal cells. The liposomes were loaded with mRNA (up to 112 µg/mL) and characterized in terms of their size (Z-average; 135.4 nm ± 1.1 nm), size distribution (polydispersity index (PDI); 0.213 ± 0.007 nm), surface charge (2.89 ± 0.27 mV), structure, lamellarity (multilamellar liposomes), and cargo capacity (>90%). The impact of freeze-drying and long-term storage of liposomal formulations was examined, and in vitro experiments on Caco-2 cells were conducted to evaluate the cytotoxicity of the liposomal formulations and demonstrate the uptake of the liposomes into cells. The efficiency of the formulations could be proven in vitro. When compared to control liposomes and 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-liposomes, the new formulations exhibited significantly enhanced uptake in Caco-2 cells, an immortalized epithelial cell line. Moreover, the cytocompatibility of the formulations could be proven by the absence of cytotoxic effects on the viability of Caco-2 cells. Hence, this liposomal drug delivery system holds significant promise for the oral delivery of mRNA.
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