Schematic illustration of the systemic delivery of macromolecules in the clinic using nanotherapeutics. After systemic administration of formulations, interaction can be with target cell surface (gold and iron oxide nanoparticles (NP)) or delivery system can be internalized. Endonuclease sensitive actives (siRNA, mRNA) are protected by encapsulation in delivery system. Target cell entry can be by interactions between targeting ligand on the surface of delivery system (surface functionalized cyclodextrin based NP) or by endocytosis (liposomes and nucleic acid coated gold NP). After endocytosis, delivery system can facilitate endosomal escape via endosome disruption. Protein expression occurs by translation of free mRNA in cytoplasm. For delivery systems with extracellular site of action, efficacy is achieved by initiating downstream signaling cascade. Cell surface ligands can be proteins or genetic material for extracellularly acting delivery systems.
