Inflammation-targeting and self-limited neutrophilic membrane-encapsulated teicoplanin for the treatment of infectious pneumonia

• Published in: Trends in biotechnology (Regular ed.)
• Main Authors: Lu, Huidan, Zhang, Kaixin, Zhang, Wanying, Zhang, Wenting, Wu, Jicheng, Ming, Xinliang, Huang, Yuqiao, Xu, Feng, Wang, Ben
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 14.06.2025
• Subjects: biomimetic nanocarriers; Internal Medicine; intracellular bacteria; MRSA; neutrophil swarming; pneumonia; intracellular bacteria; pneumonia; neutrophil swarming; biomimetic nanocarriers; MRSA
• ISSN: 0167-7799; 1879-3096; 1879-3096
• DOI: 10.1016/j.tibtech.2025.05.009

Neutrophil membrane-derived extracellular vesicles (NEVs) exhibit exceptional targeted delivery capabilities, efficiently transporting antibiotics through biological barriers to infection sites and bacterial biofilms.This biomimetic system, combining teicoplanin-loaded neutrophil membranes for targeted anti-inflammatory therapy, is particularly effective against drug-resistant infections.Teicoplanin-loaded NEVs (Teic@NEV) offer dual benefits: strong antibacterial activity and immunomodulation by reducing neutrophil swarming and inflammation.NEV-based delivery outperforms conventional therapies with lower toxicity. The platform enables precise delivery across multiple inflammatory disease models, including pneumonia, osteomyelitis, and colitis, highlighting its significant potential for clinical translation. Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia has a high clinical incidence and is associated with a significant mortality risk. The existence of intracellular pathogens and the infection-induced swarming of neutrophils exacerbate the challenges in treating pneumonia. Here, we addressed these issues by developing a platform based on neutrophilic membrane-camouflaged teicoplanin (Teic@NEV) to kill bacteria in tissue and prevent inflammatory lung injury associated with MRSA pneumonia. Teic@NEV improved the efficiency of drug entry into cells, meaningfully increasing the intracellular drug concentration in infected cells and eliminating intracellular MRSA. Moreover, Teic@NEV enhanced the penetration of teicoplanin into the biofilm and improved antimicrobial and antibiofilm activities in vitro. Surprisingly, Teic@NEV delivered teicoplanin specifically to sites of inflammation and reduced lung injury by hindering neutrophil swarming in vivo. Thus, this platform represents an effective strategy to limit neutrophil swarming and kill intracellular pathogens in patients with MRSA pneumonia, demonstrating its significant potential for use in clinical practice. [Display omitted] Neutrophil membrane-camouflaged teicoplanin (Teic@NEV) has shown promising preclinical results by utilizing neutrophil chemotaxis for targeted antibiotic delivery. However, several key challenges must be addressed before clinical translation. Current barriers include scalability limitations of the membrane compression manufacturing process, the potential immunogenicity of engineered membranes in human subjects, and the need for thorough safety evaluation in complex infection microenvironments. Overcoming these hurdles will require standardized Good Manufacturing Practice (GMP)-compliant production protocols, comprehensive immunoprofile characterization in primate models, and combinatorial efficacy testing with existing antibiotics. One promising approach to addressing potential immunogenicity is the development of an induced pluripotent stem cell (iPSC)-derived neutrophil therapeutic system, achieved through in vitro stem cell gene editing and differentiation for universal targeted therapy. The proposed iPSC-derived neutrophil platform provides an ideal resource for generating immune cells, with well-established methodologies enabling the derivation of various cell types, including neutrophils. However, this approach will require further research into stem cell differentiation controls and in vivo persistence before leveraging a neutrophil-based delivery platform for the treatment of inflammatory and infectious diseases. Teicoplanin-loaded neutrophil membrane-derived extracellular vesicles (Teic@NEV) represent a neutrophil-mimicking nanoplatform that concurrently eliminates methicillin-resistant Staphylococcus aureus (MRSA) infections and prevents inflammatory lung damage via targeted antibiotic delivery and pathological neutrophil swarm modulation, outperforming standard therapies.