The Different Cellular Entry Routes for Drug Delivery Using Cell Penetrating Peptides

The cell plasma membrane acts as a semi-permeable barrier essential for cellular protection and function, posing a challenge for therapeutic molecule delivery. Conventional techniques for crossing this barrier, including biophysical and biochemical methods, often exhibit limitations such as cytotoxicity and the risk of genomic integration when viral vectors are involved. In contrast, cell-penetrating peptides (CPPs) offer a promising non-invasive means to deliver a broad range of molecular cargoes, including proteins, nucleic acids and small molecules, into cells. CPPs, typically 5 to 30 amino acids long and rich in basic or non-polar residues, interact favourably with different cell membranes. These peptides have evolved since the discovery of the HIV-1 TAT peptide in the 1980s, expanding into various CPP families with diverse therapeutic applications. CPPs can form covalent or non-covalent complexes with their cargo, influencing their stability and efficacy. Based on their sequence properties and interactions, CPPs can be amphipathic or non-amphipathic, with distinct mechanisms of membrane penetration, such as direct penetration and endocytosis. While their uptake mechanisms are complex and not fully elucidated, ongoing optimization aims to enhance CPP specificity and efficacy. CPPs have demonstrated potential in drug delivery, gene therapy, cancer treatment and vaccine development, addressing key safety and efficiency concerns associated with viral vectors. This review explores the classification, mechanisms of action and therapeutic potential. It focuses on the intracellular vesicular trafficking of CPPs, highlighting their role as transformative tools in advancing cellular therapies and medical treatments.