An insight into cell-penetrating peptides: perspectives on design, optimization, and targeting in drug delivery systems.

The authors carried out a comprehensive review of the application of peptides known as cell-penetrating peptides (CPPs) in various drug delivery systems (DDS), with the prospect of achieving novel solutions and ideas to overcome the challenges of DDS, by making them more able to penetrate cells and biological membranes. A conceptual search was conducted in relevant literature databases (Scopus, PubMed, Web of Science, and Google Scholar) up to 1 April 2025 using keywords such as drug delivery systems, cell-penetrating peptides, CPPs, complexes, conjugates, nanoparticles, dendrimers, exosomes, liquid crystalline, liposomes, micelles, nanospheres and lipid nanoparticles. The studies demonstrate that the antimicrobial effect of drugs, including curcumin, gentamicin, and antifungal drugs like imidazoacridinone derivatives, can be enhanced when they are conjugated or complexed with CPPs. CPPs possess positive charges, which make them suitable for gene therapy applications by facilitating the delivery of plasmids and siRNAs with negative charges in modern delivery systems. Medicinal formulations containing CPPs in combination with liquid crystals or nanostructured lipid carriers (NLCs) increase drugs penetration to the skin. Additionally, several investigations showed that CPPs could have a positive impact on the pharmacokinetic and pharmacodynamic of chemotherapy agents, reducing their side effects. CPPs have significant potential in enhancing penetration, bioavailability, targeting, and optimization of DDS. By using computer modeling and designing CPPs with more desirable features and conducting more clinical studies, new methods for treating diseases and better formulations can be achieved.