Cell‐penetrating peptides (CPPs) are short peptides with significant potential in the field of drug delivery as they can enhance the cellular uptake of their attached cargo. Meanwhile, lipid nanoparticles (LNPs) are important nanocarriers for various drugs as they provide stability to drug molecules and their surface can be modified with different ligands for targeted delivery. Consequently, modification of different LNPs with CPPs is an important approach to improve intracellular drug delivery and targeting. In this chapter, we briefly introduce CPPs, their types, and the mechanisms of their uptake. We also introduce LNPs and discuss their applications in drug delivery. We then focus on the modification of different LNPs with CPPs and the potential applications of these promising nanocarriers in intracellular delivery as well as in tumor and liver targeting. We finally discuss some strategies …

mRNA delivery has recently gained substantial interest for possible use in vaccines. Recently approved mRNA vaccines are administered intramuscularly where they transfect antigen-presenting cells (APCs) near the site of administration, resulting in an immune response. The spleen contains high numbers of APCs, which are located near B and T lymphocytes. Therefore, transfecting APCs in the spleen would be expected to produce a more efficient immune response, but this is a challenging task due to the different biological barriers. Success requires the development of an efficient system that can transfect different immune cells in the spleen. In this study, we report on the development of mRNA-loaded lipid nanoparticles (LNPs) targeting immune cells in the spleen with the goal of eliciting an efficient immune response against the antigen encoded in the mRNA. The developed system is composed of mRNA loaded in LNPs whose lipid composition was optimized for maximum transfection into spleen cells. Dendritic cells, macrophages and B cells in the spleen were efficiently transfected. The optimized LNPs produced efficient dose-dependent cytotoxic T lymphocyte activities that were significantly higher than that produced after local administration. The optimized LNPs encapsulating tumor-antigen encoding mRNA showed both prophylactic and therapeutic antitumor effects in mice.