Cell-penetrating peptides as facilitators of cargo-specific nanocarrier-based drug delivery

Nanocarriers (NCs) have emerged as a prime tool for drug delivery, with their highly tunable properties allowing for targeting down to the organelle level. For successful drug delivery, NCs of all administration routes face challenges to reaching target sites in the form of various biological barriers. A prominent one of these barriers is cellular uptake. Conjugation of cell-penetrating peptides (CPPs) to NC surfaces has been found to overcome this barrier, as such enhancing percent accumulation in the target site. Recently, novel CPPs have been found to enhance efficacy of NC platforms via their ability to aid in overcoming additional barriers such as the mucus layer, immune clearance, and non-specific accumulation. The design of NC-CPP drug delivery platforms involves consideration to the synergy between the NC type, cargo, target cell, and CPP. This review dives into recent developments of these platforms and into novel CPPs for NC drug delivery, also highlighting areas of future research. We cover a broad swath of the field, touching on novel instances and trends investigating the use of newly designed CPPs modulated for recognizing specific ligands for active targeting, NC-CPP combinations which tackle biological barriers such as the blood-brain barrier, and those with unique cargos from nucleic acids to proteins.