Self-Assembling Peptide Dendron Nanoparticles with High Stability and a Multimodal Antimicrobial Mechanism of Action.
Self-assembling nanometer-scale structured peptide polymers and peptide dendrimers have shown promise in biomedical applications due to their versatile properties and easy availability. Herein, self-assembling peptide dendron nanoparticles (SPDNs) with potent antimicrobial activity against a range of bacteria were developed based on the nanoscale self-assembly of an arginine-proline repeat branched peptide dendron bearing a hexadecanoic acid chain. The SPDNs are biocompatible, and our most active peptide dendron nanoparticle, C16-3RP, was found to have negligible toxicity after both in vitro and in vivo studies. Furthermore, the C16-3RP nanoparticles showed excellent stability under physiological concentrations of salt ions and against serum and protease degradation, resulting in highly effective treatment in a mouse acute peritonitis model. Comprehensive analyses using a series of biofluorescence, microscopy, and transcriptome sequencing techniques revealed that C16-3RP nanoparticles kill Gram-negative bacteria by increasing bacterial membrane permeability, inducing cytoplasmic membrane depolarization and drastic membrane disruption, inhibiting ribosome biogenesis, and influencing energy generation and other processes. Collectively, C16-3RP nanoparticles show promising biocompatibility and in vivo therapeutic efficacy without apparent resistance development. These advancements may facilitate the development of peptide-based antibiotics in clinical settings.
['Lai|Zhenheng|Z|0000-0002-6450-4051', 'Jian|Qiao|Q|', 'Li|Guoyu|G|', 'Shao|Changxuan|C|', 'Zhu|Yongjie|Y|', 'Yuan|Xiaojie|X|', 'Chen|Hongyu|H|', 'Shan|Anshan|A|0000-0003-2830-7509']
D000818:Animals D000900:Anti-Bacterial Agents D000890:Anti-Infective Agents D050091:Dendrimers D051379:Mice D053758:Nanoparticles D010455:Peptides
peptide dendron stability mechanism of action in vivo efficacy self-assembling nanoparticles