Stimuli-Responsive Codelivery of Oligonucleotides\nand Drugs by Self-Assembled Peptide Nanoparticles

Abstract

Ever more emerging combined treatments\nexploiting synergistic effects\nof drug combinations demand smart, responsive codelivery carriers\nto reveal their full potential. In this study, a multifunctional stimuli-responsive\namphiphilic peptide was designed and synthesized to self-assemble\ninto nanoparticles capable of co-bearing and -releasing hydrophobic\ndrugs and antisense oligonucleotides for combined therapies. The rational\ndesign was based on a hydrophobic l-tryptophan-d-leucine repeating unit derived from a truncated sequence of gramicidin\nA (gT), to entrap hydrophobic cargo, which is combined with a hydrophilic\nmoiety of histidines to provide electrostatic affinity to nucleotides.\nStimuli-responsiveness was implemented by linking the hydrophobic\nand hydrophilic sequence through an artificial amino acid bearing\na disulfide functional group (H3SSgT). Stimuli-responsive peptides\nself-assembled in spherical nanoparticles in sizes (100–200\nnm) generally considered as preferable for drug delivery applications.\nResponsive peptide nanoparticles revealed notable nucleotide condensing\nabilities while maintaining the ability to load hydrophobic cargo.\nThe disulfide cleavage site introduced in the peptide sequence induced\nresponsiveness to physiological concentrations of reducing agent,\nserving to release the incorporated molecules. Furthermore, the peptide\nnanoparticles, singly loaded or coloaded with boron-dipyrromethene\n(BODIPY) and/or antisense oligonucleotides, were efficiently taken\nup by cells. Such amphiphilic peptides that led to noncytotoxic, reduction-responsive\nnanoparticles capable of codelivering hydrophobic and nucleic acid\npayloads simultaneously provide potential toward combined treatment\nstrategies to exploit synergistic effects.