菌膜及其内部持留菌对抗生素高度耐受，导致持续感染并增加细菌耐药发生的风险。铜绿假单胞菌常以菌膜形式附着于气道黏液中，引发顽固性肺部感染，并且通过调控群体感应（QS）分泌毒力因子造成肺组织严重损伤。我们基于菌膜与持留菌复杂的依存关系，从降低细菌致病性出发，结合菌膜定植特点，构建智能型脂质聚合物纳米粒（LPNs）。LPNs以果胶硫酸酯/妥布霉素纳米复合物为内核，N-乙酰半胱氨酸修饰的DSPE（DSPE-NAC）和鼠李糖酯构成混合脂质外壳，装载呋喃酮衍生物BF8。DSPE-NAC破坏黏液结构，促进LPNs穿透黏液到达菌膜定植部位；鼠李糖酯破坏菌膜促使菌膜分散，促代谢剂BF8刺激分散的持留菌恢复敏感性，然后被妥布霉素杀灭。BF8同时发挥QS抑制作用阻断菌膜再生及减少毒力因子引起的损伤。果胶硫酸酯作为最后防线抑制残余菌再黏附提高菌膜清除率。本智能型LPNs有望拓展至具类似菌膜定植特征的持续感染领域

Biofilm and persisters in it are highly tolerant to antibiotics, resulting in persistent infection and increasing the risk of bacterial resistance. P. aeruginosa often adheres to the mucus of respiratory tract in the form of bacterial biofilm, which causes intractable lung infection and severe lung injury related to virulence factors by regulating quorum-sensing (QS). According to the structure and colonization characteristics of P. aeruginosa biofilm, we constructed intelligent lipid polymer nanoparticles (LPNs). The core of LPNs was pectin sulfate / tobramycin nanoparticles. N-acetylcysteine-modified DSPE (DSPE-NAC) and rhamnolipid formed a mixed lipid shell in which furanone derivative BF8 was involved. DSPE-NAC could destroy the structure of mucus and help LPNs penetrate the mucus to arrive the site of bacterial biofilm colonization. Rhamnolipid destructed the bacterial biofilm and made interior bacteria dispersed. The metabolic activator BF8 stimulated the sensitivity of retained bacteria and made it easily killed by tobramycin. BF8 also inhibited biofilm re-formation and reduced the damage caused by virulence factors. Pectin sulfate could inhibit the reattachment and colonization of residual bacteria and further increase the clearance rate. Due to the similar structure-colonization properties of different bacterial biofilm, this intelligent LPNs is expected to be extended to other areas of persistent infection.