A review article on cell-penetrating peptides as nanocarriers for intracellular drug delivery

Abstract

Cell-penetrating peptides (CPPs) have emerged as a highly promising class of nanocarriers capable of overcoming cellular barriers to deliver therapeutic molecules intracellularly. CPPs, characterized by their cationic, amphipathic, or hydrophobic nature, facilitate efficient translocation across lipid bilayers, transporting diverse cargoes such as nucleic acids, proteins, and nanoparticles directly into cells. This review systematically explores the classification, structural characteristics, and uptake mechanisms of CPPs, emphasizing their conjugation with nanocarriers to enhance therapeutic efficacy. Significant applications of CPP-based systems across various biomedical fields, including cancer therapy, neurological disorders, and genetic diseases, are discussed. Despite their substantial potential, CPPs face critical challenges such as non-specific cellular uptake, endosomal entrapment, proteolytic instability, and potential cytotoxicity. Recent advancements addressing these issues through targeted design, stimuli-responsive constructs, and computational modeling demonstrate promising progress towards clinical translation. The review concludes with future perspectives on leveraging CPPs in RNA therapeutics, CRISPR gene editing, theranostics, and precision medicine.