Poly(Amino Acid) Nanoparticles On-Site Deliver Drug Combinations For The Elimination Of Intracellular Bacteria

Recurrent infections caused by intracellular bacteria can lead to serious complications.However,drug combination as a common strategy for the treatment of intracellular bacterial infections is greatly hampered by differential drug metabolism,uptake and different internalization pathways and subcellular organelle residency at the cellular level during the specific treatment process.Herein,this study proposes a strategy for the synergistic intracellular bactericidal action of combination drugs.This strategy is achieved by using a drug delivery system（DDS）with dual macrophage/intracellular bacterial targeting capabilities to deliver drug combinations on-site,ultimately resulting in efficient clearance of intracellular bacterial infections through intracellular drug synergism.The main elements are as follows:1.The hydrophobic coreα-N-acryloyl-phenylalanine（denoted as F）was first introduced by PET-RAFT polymerization technique,followed by the successful introduction of the hydrophilic componentβ-N-acryloyl-α-Boc-D-aminoalanine(denoted as A_Boc)and2-（2’,3’,4’,6’-tetra-O-acetyl-α-D-mannosyl）ethyl acrylate(denoted as M_OAc)by classical copolymerization procedure,and the dual targeting function of DDS by macrophage/intracellular bacteria was demonstrated by co-localization experiments.2.Extracellularly,there is a synergistic bactericidal effect between vancomycin and curcumin.Vancomycin and curcumin could be successfully encapsulated in DDS at predetermined doses and released in a uniform and long-term pattern.Meanwhile,the extracellular antibacterial results demonstrated that the NPs encapsulating vancomycin and curcumin exhibited the best extracellular antibacterial effect due to the drug synergistic effect.3.The results evaluated by the intracellular bacterial model revealed that DDS was internalized into macrophages through an energy-dependent mannose receptor ligand-mediated macrophage drinking mode with specific recognition,which not only unified the drug internalization pathway but also achieved rapid internalization effect in macrophages.The drug was effectively delivered to the site of bacterial infection through dual-targeting ability to achieve efficient intracellular drug synergy.Compared with other controls,（Van+Cur）@F（AM）NPs showed the best intracellular bactericidal effect.In addition,evaluation by a mouse abdominal infection model revealed that DDS was able to modulate body immunity by regulating pro-inflammatory factors,which ultimately further improved the intracellular bacterial synergistic treatment effect.