Cell membrane derived liposomes loaded with DNase I target neutrophil extracellular traps which inhibits colorectal cancer liver metastases

Abstract

Neutrophil extracellular traps (NETs) are web-like chromatin structures that are coated with granule proteins and trap microorganisms. However, NETs can damage the host tissue, contribute to the development of autoimmunity and lead to other dysfunctional outcomes in noninfectious diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), diabetes, atherosclerosis, vasculitis, thrombosis, and cancer. As a potential therapeutic approach, targeted ablation of neutrophil extracellular traps is of utmost importance for the treatment of NET-associated diseases. Here, the specific interaction between CCDC25 and NETs was exploited to produce biomimetic CCDC25-overexpressing cell membrane hybrid liposomes capable of targeting NETs in NET-associated diseases. The hybrid liposomes were constructed by fusing cell membrane nanovesicles derived from genetically engineered cells, which stably express CCDC25, and the resulting cell membrane hybrid liposomes exhibited enhanced affinity for NETs in two different NET-associated disease models. Furthermore, after encapsulation of DNase I in the liposomes, the nanoformulation efficiently eliminated NETs and significantly suppressed the recruitment of neutrophils. Overall, we present a bionic nanocarrier that specifically targets NETs in vivo and successfully inhibits colorectal cancer liver metastases; importantly, this could be a promising therapeutic approach for the treatment of NET-associated diseases.

Keywords: Genetic engineering; Liver metastases; Neutrophil extracellular traps; Premetastatic niche; Targeted delivery.