New generation of cell-penetrating peptides: Functionality and potential clinical application

Area of Science:

• Biotechnology
• Molecular Biology
• Drug Delivery Systems

Background:

• Cell-penetrating peptides (CPPs) facilitate cargo transport into live cells.
• First-generation CPPs faced limitations in selectivity, stability, and endosomal escape.
• New CPP generations are engineered for enhanced properties.

Purpose of the Study:

• To review advancements in cell-penetrating peptides (CPPs).
• To highlight optimized CPPs for improved drug delivery and therapeutic applications.
• To provide guidance on selecting or designing CPPs for specific tasks.

Main Methods:

• Development of second-generation CPPs through natural derivation or multivalent structure combinations.
• Engineering hybrid CPP structures with sequences for endosomal escape, homing, and targeted activation.
• Conjugation of CPPs to nanoparticles for enhanced penetration and stability.

Main Results:

• New CPPs demonstrate high internalization efficiency, cell/tissue selectivity, and endosomal escape.
• Specific CPPs exhibit innate tumor selectivity and cytotoxic effects.
• CPPs enable drug transport through challenging barriers like the blood-brain barrier (BBB) and into 3D cultures.
• CPPs facilitate non-invasive delivery methods (sprays, creams, drops).

Conclusions:

• Optimized CPPs offer significant improvements over earlier generations.
• CPP efficacy is context-dependent, influenced by target tissue, cargo, and coupling methods.
• Careful selection and design of CPPs are crucial for successful therapeutic applications.