Oligonucleotide loaded polypeptide‐peptide nanoparticles towards mitochondrial‐targeted delivery

Nanoparticles (NPs) consisting of biodegradable and biocompatible polymers may have the ability to deliver a cargo to specific tissue, cell type, and organelle. Various diseases, which are linked to mitochondrial genome (mtDNA) mutations and have no effective treatments, may be approached by gene therapy strategies. In this study, we adapted the recently developed mitochondria delivering polypeptide‐peptide nanoparticles (PoP‐NPs) system to carry an oligonucleotide cargo to the proximity of the mitochondria. PoP‐NPs are formulated by self‐assembly of the negatively charged polypeptide, poly gamma glutamic acid (γ‐PGA), with an amphiphilic and cationic β‐sheet peptide (PFK). Here, we show that PFK interacts favorably with oligonucleotides and thereby enables the formation of DNA‐loaded PoP‐NPs (DNA‐PoP‐NPs). DNA‐PoP‐NPs could be assembled with different peptide to oligonucleotide (N/P) ratios, and their targeting to the proximity of mitochondria in cell culture could be facilitated through NPs coating with PFK peptide.