Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery

Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)(3), RH-(GFLG)(3)). The self-assembled RH-(GFLG)(3) globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)(3) nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD ((RH)-R-L-(D)(GFLG)(3)), DL ((RH)-R-D-L(GFLG)(3)), and DD ((RH)-R-D-(D)(GFLG)(3)). The RH-(GFLG)(3) nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)(3) nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)(3) peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications.

Automated summary

Self-assembled peptide nanostructures are gaining attention as drug delivery systems due to their enhanced biocompatibility and biodegradability compared to polymer-based carriers. In this study, an enzyme-responsive peptide nanoparticle system was introduced, which showed effective controlled release of cargo molecules. The system exhibited good cellular uptake and biocompatibility, and demonstrated superior anticancer effects compared to the control groups.