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Unveiling the secrets of cell-penetrating peptides: direct penetration or via endocytosis?
Cell-penetrating peptides (CPPs) are short peptides that can facilitate the entry of a variety of molecules into cells, ranging from nanoparticles to small chemical compounds and even large DNA fragments. CPPs achieve transport and delivery of spheroids by chemically linking or non-covalently interacting with cargoes. These peptides are important tools in research and medical treatment, but their use is currently limited by a lack of cellular specificity and a poor understanding of their uptake patterns.
CPPs are diverse in their transport and have shown their potential as drug delivery vehicles, particularly in cancer therapy and viral suppression.
Mechanisms of cell penetrating peptides
The transmembrane transport of cell-penetrating peptides relies on three potential mechanisms: direct penetration, endocytosis, and transport through transient structures. The exact understanding of these mechanisms is still under investigation.
Most early studies believed that polycationic CPPs enter cells through an energy-independent process involving electrostatic interactions with negatively charged phospholipids.
Direct penetration mechanism
For the direct penetration of CPP, researchers have proposed several models to explain the biophysical mechanism. Some of these models propose that CPPs may interact electrostatically with membranes, altering membrane structure to facilitate their entry into cells. However, recent studies have highlighted the limitations of this model and the critical role of endocytosis in the CPP uptake process.
The role of endocytosis
Endocytosis is a cellular uptake process that involves the inward folding of the cell membrane to acquire foreign substances. Studies have shown that endocytosis is a major mechanism of cellular internalization and that the behavior of different CPPs during endocytosis displays multiple mechanisms occurring simultaneously. This has been demonstrated particularly for the penetrating peptides penetratin and transportan.
Endocytosis not only involves energy, but also allows different uptake pathways to alternate simultaneously.
Transport through the formation of transient structures
The last mechanism is based on the formation of reverse micelles. In this model, CPPs bind to negatively charged phospholipids, and the resulting inverted micelles can maintain an aqueous environment within the lipid bilayer. Such a structure remains controversial in the literature, as the asymmetric distribution would generate a favorable electric field that could drive the internalization process.
Applications of cell penetrating peptides
Cell-penetrating peptides have shown significant potential in drug delivery and treatment of various diseases. Especially in the delivery of nucleic acids, CPP-nucleic acid complexes have become a powerful tool that can not only solve the problem of transporting high molecular weight nucleic acids, but also effectively maintain their biological activity.
For example, the successful delivery of short interfering RNA (siRNA) and antisense oligonucleotides (asONs) demonstrates the great application potential of CPPs in modern medicine.
Transport of contrast media
CPPs are also used as delivery vehicles for contrast agents in cancer diagnosis. Through these contrast agents, researchers can effectively mark tumor cells and obtain more accurate diagnostic data. Recent studies have found that the design of β- or γ-amino acid contrast agents using asymmetric amino acids can improve the stability and efficacy of penetrating peptides.
For the future of medical technology, the potential of cell-penetrating peptides still has many unknown challenges and options. How do you think future research will change our understanding and application of cell-penetrating peptides?
