Hepatoma is a serious public health concern. New attempts are urgently needed to solve this problem. Melittin, a host defense peptide derived from the venom of honeybees, has noteworthy hemolysis and non-specific cytotoxicity in clinical applications. Here, the self-assembly of melittin and vitamin E-succinic acid-(glutamate)12 (VG) was fabricated via noncovalent π-stacking and hydrogen bonding interactions by an environment-friendly method without the use of “toxic” solvents. As expected, the designed self-assembly (denoted as M/VG nanoparticles) exhibits a uniform morphology with a particle size of approximately 60 nm and a zeta potential of approximately −26.8 mV. Furthermore, added VG significantly decreased hemolytic activity, increased tumor-targeted effects, promoted the cellular uptake, and accelerate apoptosis. Our research provides a promising strategy for the development of natural self-assembled biological peptides for clinical application, particularly for transforming toxic peptides into safe therapeutic systems.

Hepatoma is a serious public health concern. New attempts are urgently needed to solve this problem. Melittin, a host defense peptide derived from the venom of honeybees, has noteworthy hemolysis and non-specific cytotoxicity in clinical applications. Here, the self-assembly of melittin and vitamin E-succinic acid-(glutamate)12 (VG) was fabricated via noncovalent π-stacking and hydrogen bonding interactions by an environment-friendly method without the use of “toxic” solvents. As expected, the designed self-assembly (denoted as M/VG nanoparticles) exhibits a uniform morphology with a particle size of approximately 60 nm and a zeta potential of approximately − 26.8 mV. Furthermore, added VG significantly decreased hemolytic activity, increased tumor-targeted effects, promoted the cellular uptake, and accelerate apoptosis. Our research provides a promising strategy for the development of natural self-assembled biological peptides for clinical application, particularly for transforming toxic peptides into safe therapeutic systems.