Nanoparticle Targeting Strategies for Lipid and Polymer-Based Gene Delivery to Immune Cells In Vivo

Lipid nanoparticles and polymeric nanoparticles are promising biomaterial platforms for robust intracellular DNA and mRNA delivery, highlighted by the widespread use of nanoparticle- (NP) based mRNA vaccines to help end the COVID-19 pandemic. Recent research has sought to adapt this nanotechnology to transfect and engineer immune cells in vivo. The immune system is an especially appealing target due to its involvement in many different diseases, and ex vivo-engineered immune cell therapies like chimeric antigen receptor (CAR) T therapy have already demonstrated remarkable clinical success in certain blood cancers. Although gene delivery can potentially address some of the cost and manufacturing concerns associated with current autologous immune cell therapies, transfecting immune cells in vivo is challenging. Not only is extrahepatic NP delivery to lymphoid organs difficult, but immune cells like T cells have demonstrated particular resistance to transfection. Despite these challenges, the modular nature of NPs allows researchers to examine critical structure–function relationships between a particle's properties and its ability to specifically engineer immune cells in vivo. Herein, several nanomaterial components are outlined, including targeting ligands, nucleic acid cargo, chemical properties, physical properties, and the route of administration to specifically target NPs to immune cells for optimal in vivo transfection.