A Framework Nucleic Acid Based Robotic Nanobee for Active Targeting Therapy

DNA nanotechnology has provided new strategies and platforms for cargo delivery. However, DNA‐based nanostructures utilized for cargo delivery have mainly focused on static structures and passive targeting. Here, inspired by honeybee's natural reaction to hazards, a melittin loaded tetrahedron framework nucleic acid (tFNA) nanostructure, for active targeting therapy as a “nanobee” is developed. Upon exposure to target proteins on the cell membrane, the tFNA exoskeleton goes through conformation change, leading to the selective release of melittin from the exoskeleton and the consequent selective lethal effect. As a result, the active targeting of the nanobee to tumor cells is achieved. At the same concentrations of melittin, the nanobee exhibits significantly higher and more selective cytotoxicity against target cells than free melittin molecules, whereas the inactive nanobee shows neglectable lethal effect. Notably, the complete encapsulation of melittin in the tFNA exoskeleton is confirmed by the combination of experimental screening and molecular dynamic analysis, which is proposed to be the origin of the minimized off‐target effects of nanobee. This nanobee concept offers a strategy that may be extended to various dynamic stimuli‐responsive cargo delivery systems, to enhance cargo stability and decrease severe off‐target effects. Inspired by the honeybee's natural reaction to hazards, a framework nucleic acid (FNA) nanostructure‐based nanobee is fabricated for active melittin delivery. To minimize the off‐target effects, a combination of experimental screening and MD analysis is employed to ensure stable melittin encapsulation into the stimuli‐responsive FNA exoskeleton. Active targeting therapy is achieved with the thus fabricated nanobee in vivo.