Molecular and supramolecular engineering on lipopeptide-based hole-punching nanotoxins to trigger multimodal death of drug-resistant tumors: Apoptosis, necrosis and autophagy

Discovering bioactive and efficient new agents for broad-spectrum multidrug resistance reversal is a worldwide challenge in the biomedical field. Herein, bioactive nanomaterials assembled from specially-designed lipopeptides are developed as a novel type of hole-punching nanotoxins to trigger multimodal tumor death for multidrug resistance reversal in vitro and in vivo. The dendritic arginine-rich peptides as hydrophilic parts could incorporate with multivalent scaffolds and multiple-interaction residues to boost membrane-binding intensity, and cholesterol as hydrophobic blocks are hopeful to improve and ameliorate membrane-targeting/inserting ability against drug-resistant tumor membranes. The amphiphilic lipopeptides are designed to drive supramolecular self-assembly into nanostructures for improving hole-punching potential and stability. As envisaged, these lipopeptide-based nanotoxins could maintain high stability, obtain strong hole-punching activity and trigger multimodal tumor death with 80.3% TUNEL-positive apoptotic cells, 97.8% PARP-positive necrotic cells and 71.0% LC3-positive autophagic cells for multidrug resistance reversal in vivo. This work opens a new opportunity to develop new-style toxins for antitumor treatment, and the lipopeptide-based nanotoxins are expected to be a candidate agent for dealing with multidrug resistance.