Xu Mao, Yu Shihui, Li Pengyu, Chen Yili, Chen Yujun, Pan Jieyi, Deng Xin, Hu Haiyan
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
J Control Release. 2025 Feb 10;378:588-604. doi: 10.1016/j.jconrel.2024.12.040. Epub 2024 Dec 25.
Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRP. aeruginosa) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation" and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N-acetylcysteine-ε-poly-l-lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro. Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDRP. aeruginosa biofilms associated infections by disintegrating the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation".
多重耐药铜绿假单胞菌（MDRP. aeruginosa）生物膜引起的慢性肺部感染的治疗挑战，这是由于抗生素耐药性显著增强所致。这种耐药性是由外膜通透性降低、生物膜屏障以及毒力因子的过度分泌驱动的。气道中增厚的黏液阻碍抗生素渗透，为生物膜提供滋生地，从而加剧感染，使问题更加严重。此外，生物膜募集大量免疫细胞，导致慢性炎症和肺组织损伤。反过来，受损的气道进一步促进细菌定植和黏液分泌增加。为了彻底瓦解“增厚的黏液、致密的生物膜和过度的炎症”这一顽固的三联征并解决耐药问题，研发了定制的多层纳米颗粒（NPVC/PBIP NPs）。NPVC/PBIP NPs通过香草醛 - 壳聚糖两亲聚合物负载多黏菌素B - 亚油酸离子对的自组装构建而成。然后通过静电相互作用在香草醛 - 壳聚糖纳米颗粒表面逐层包覆聚天冬氨酸和N - 乙酰半胱氨酸 - ε - 聚 - L - 赖氨酸。正如预期的那样，NPVC/PBIP NPs上的NAC单元有效稀释了人类临床痰液和猪痰液，实现了快速的痰液渗透，随后是生物膜渗透。NPVC/PBIP NPs在体外实现了对成熟生物膜超过99%的根除。此外，它们有效抑制毒力因子的产生和细菌再黏附（生物膜再形成），同时表现出卓越的抗炎和抗氧化活性。在慢性肺部感染模型中，NPVC/PBIP NPs显著稀释气道黏液，使细菌载量降低99.7%，减轻炎症细胞浸润，并使肺组织损伤最小化。总之，NPVC/PBIP NPs代表了一种通过瓦解“增厚的黏液、致密的生物膜和过度的炎症”这一顽固三联征来管理与MDRP. aeruginosa生物膜相关感染的新颖且有前景的策略。
