DNA nanotube-carrying antimicrobial peptide confers improved anti-infective therapy

Antimicrobial peptides (AMPs) represent a good alternative for treating infections to overcome increasing antibiotic resistance problems. DNA nanostructures have been utilized as the delivery carrier of AMPs to enhance their performance, but mechanisms of action remain largely unclear. In this work, DNA nanotube (DNT) was chosen as a preferred carrier of AMPs owing to its high binding affinity and loading capacity, and an engineered broad-spectrum AMP named RP557 was screened as the cargo though molecular simulation and subsequent loading experiments. RP557 molecules were then loaded onto DNT through electrostatic interaction to construct RP557@DNT nanocomplex for improved anti-infective therapy. Loaded RP557 possessed the lower cytotoxicity to fibroblasts and epithelial cells and the higher compatibility to red blood cells relative to free RP557 in vitro, and RP557@DNT displayed the highly favored biodegradability and biosafety at the animal level. In addition, compared to free RP557, RP557@DNT endowed better bactericidal activity in vitro and in vivo because loaded RP557 exhibited higher resistance to serum protease degradation and controlled release onto bacterial cell membrane. The high therapeutic effect of RP557@DNT primarily depended on the acceleration of inflammation resolution (involving the reduction in proinflammatory factor production, innate immune cell recruitment, and adaptive immunity) and tissue repair (involving the up-regulation of multiple epidermal and dermal repair pathways). In summary, RP557@DNT showed significantly enhanced anti-enzymolysis, antibacterial activity, and biosafety relative to free RP557, and thus it represented a high-efficiency antibiotics-alternative strategy for treating refractory infections.