Coassembly of Enantiomeric Peptides Inside Mitochondria for Supramolecular Cancer Therapy

Abstract

Nanoscopic delivery vehicles capable of encapsulating drug molecules and releasing them in response to external stimuli are of great interest due to implications in therapeutic applications. Polymeric micellar assemblies are promising scaffolds to overcome many of the problems faced with traditional chemotherapies because of their capacity for non-covalent, hydrophobic guest molecule binding. However, the stability of encapsulation with such self-assembled systems is limited during blood circulation because of a requisite concentration for assembly formation. Thus, deliberate molecular design for stable encapsulation, targeting and triggered release is required. For this purpose, we have developed a facile synthetic method for highly stable, polymeric nanogels or polymer-caged hollow nanoparticles using a simple intra/inter-chain crosslinking reaction. We show a simple method for the preparation of biocompatible nanovehicles that provides the ability to encapsulate hydrophobic or hydrophilic drug molecules. We can control the size of the nano-carriers and release kinetics depending on crosslinking in responsive to stimuli. Nano-carriers showed great stability to encapsulate drug molecules and drugs were only released inside cell. In addition, we can use surface modified nano-carriers for target delivery system. Cancer targeting nanomaterials have been extensively attempted by coating their surfaces with small molecules, peptides, proteins, and antibodies, but the tumor targeting and therapeutic efficacy still exhibits only a modest improvement due to deleterious interactions of nanomaterials with proteins (protein corona formation). We developed mesoporous nanoparticles pre-coated with a recombinant fusion protein featuring HER2-binding affibody molecule and glutathione-S-transferase. Upon stabilized in preferred orientations on nanoparticle, the pre-coated proteins as a corona minimize interactions with serum proteins to prevent the clearance of these particles by macrophages, while ensuring their targeting function in vitroand in vivo. These findings can provide a new insight into intra-mitochondrial assembly for the regulation of cellular functions and a therapeutic approach and new targeting platform for the biomedical community since numerous functional proteins can be installed by the similar fashion.