Improving the endosomal escape of cell-penetrating peptides and their cargos: strategies and challenges.
Cell penetrating peptides (CPPs) can deliver cell-impermeable therapeutic cargos into cells. In particular, CPP-cargo conjugates tend to accumulate inside cells by endocytosis. However, they often remain trapped inside endocytic organelles and fail to reach the cytosolic space of cells efficiently. In this review, the evidence for CPP-mediated endosomal escape is discussed. In addition, several strategies that have been utilized to enhance the endosomal escape of CPP-cargos are described. The recent development of branched systems that display multiple copies of a CPP is presented. The use of viral or synthetic peptides that can disrupt the endosomal membrane upon activation by the low pH of endosomes is also discussed. Finally, we survey how CPPs labeled with chromophores can be used in combination with light to stimulate endosomal lysis. The mechanisms and challenges associated with these intracellular delivery methodologies are discussed.
Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA.
Alfredo
A
Erazo-Oliveras
Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA.
Nandhini
N
Muthukrishnan
Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA.
Ryan
R
Baker
Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA.
Ting-Yi
TY
Wang
Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA.
Jean-Philippe
JP
Pellois
cell-penetrating peptide; endosomal escape; multivalent peptides; pH-dependent membrane-active peptides; photochemical internalization