Wang Guowei, Zhang Chengyue, Huang Zixuan, Chen Jifan, Chen Hongjian, Lin Tao, Zhou Zhuxian, Gu Ning, Huang Pintong
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China.
State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou, 310030, China.
Adv Mater. 2025 Jan;37(1):e2411092. doi: 10.1002/adma.202411092. Epub 2024 Oct 27.
Biofilm-associated surgical site infection (BSSI) is a common and grievous postoperative complication lacking effective remedies, mainly due to the poor drug accumulation and penetration in the biofilms featured by dense extracellular polymeric substances (EPSs). Here, it is found that the vascular cell adhesion molecule-1 (VCAM1) is highly overexpressed in the vascular cells of BSSI. It is proposed that the combination of VCAM1-mediated transcytosis and ultrasonic cavitation can consecutively overcome the biological barriers of vascular endothelial cells and EPS for biofilm eradication. To demonstrate the feasibility, a VCAM1-targeted and ultrasound (US)-activated liposome (LPCOTML) loaded with a reactive-oxygen-species (ROS)-responsive lipoid prodrug of oleoyl meropenem, sonosensitizer of lipoid Ce6, and perfluoropentane is developed. LPCOTML can recognize the receptors on vascular cells, and initiate receptor-mediated transcytosis for transendothelial transport into the BSSI periphery. LPCOTML subsequently transforms from nanoparticle into microbubble via liquid-gas phase transition under US irradiation, triggering strong ultrasonic cavitation to blow up the EPS and deeply penetrate the biofilms. The sonosensitizer Ce6 induces ROS production under US irradiation and triggers the release of meropenem to induce potent antibacterial effect in a BSSI model. This study presents an effective strategy to tackle the biological barriers in BSSI via combining receptor-mediated transcytosis and ultrasonic cavitation.
生物膜相关手术部位感染（BSSI）是一种常见且严重的术后并发症，缺乏有效的治疗方法，主要原因是药物在由致密细胞外聚合物（EPS）构成的生物膜中蓄积和渗透较差。在此，研究发现血管细胞黏附分子-1（VCAM1）在BSSI的血管细胞中高度过表达。提出VCAM1介导的转胞吞作用与超声空化相结合可连续克服血管内皮细胞和EPS的生物屏障以根除生物膜。为证明其可行性，开发了一种靶向VCAM1且经超声（US）激活的脂质体（LPCOTM），其负载了具有活性氧（ROS）响应性的油酰美罗培南类脂质前药、类脂质Ce6声敏剂和全氟戊烷。LPCOTM可识别血管细胞上的受体，并启动受体介导的转胞吞作用以跨内皮转运至BSSI周边。随后，LPCOTM在US照射下通过液-气相转变从纳米颗粒转变为微泡，引发强烈的超声空化以破坏EPS并深入穿透生物膜。声敏剂Ce6在US照射下诱导ROS产生，并触发美罗培南的释放，从而在BSSI模型中产生强效抗菌作用。本研究提出了一种通过结合受体介导的转胞吞作用和超声空化来克服BSSI中生物屏障的有效策略。
