CPP- and TPP-functionalized nanocarriers offer advanced strategies for overcoming biological barriers in drug delivery

A significant hurdle in pharmaceutical administration is the insufficient permeability of cellular membranes and other biological barriers, which limits drug efficacy. Traditional drug delivery methods often struggle to achieve targeted and efficient transport across these formidable obstacles, leading to suboptimal therapeutic outcomes and increased systemic side effects. Cell-penetrating peptides (CPPs) and tumor-penetrating peptides (TPPs) represent a promising class of biological carriers capable of traversing these natural barriers, offering a pathway to enhance drug delivery and improve therapeutic indices.

This comprehensive review systematically synthesizes existing literature on the bio-interfacial design of Cell-Penetrating Peptides (CPPs) and Tumor-Penetrating Peptides (TPPs) functionalized nanocarriers. The authors meticulously analyzed various studies to elucidate the underlying mechanisms by which these peptides facilitate barrier-limited delivery. They established key design rules for optimizing nanocarrier performance and explored diverse applications across different biological barriers, including the blood-brain barrier, intestinal barrier, and tumor microenvironment. The review integrates insights from in vitro and in vivo models to provide a holistic understanding of this rapidly evolving field.

The review identified that CPPs and TPPs significantly enhance the cellular uptake and transcellular transport of conjugated therapeutic agents by interacting with cell membranes through various mechanisms, including direct penetration, endocytosis, and receptor-mediated pathways. Key design rules for effective nanocarrier functionalization were elucidated, emphasizing factors like peptide sequence, charge, hydrophobicity, and conjugation chemistry. The authors highlighted that CPPs-engineered PLGA nanocarriers demonstrate enhanced drug delivery efficiency by overcoming barriers like the blood-brain barrier and tumor stroma. They found that:

The bio-interfacial design of CPP/TPP-functionalized nanocarriers is critical for modulating their interaction with biological barriers, enabling precise control over drug release and targeting. Specific applications ranged from improved delivery of nucleic acids and proteins to enhanced chemotherapy efficacy in solid tumors. The review also detailed how TPPs specifically exploit the unique characteristics of the tumor microenvironment to achieve selective accumulation and penetration.