Neutrophil-Derived Extracellular Vesicles for Facile Delivery of Diagnostic Agents to Tumor Microenvironments

Targeted delivery of diagnostic and therapeutic agents to tumor microenvironments using nanoparticles improves the efficacy of these agents and reduces their unwarranted side effects. Numerous synthetic nanoparticle systems have been designed for this very purpose, but few have translated clinically due to poor efficacy-to-cost and efficacy-to-toxicity ratios. Biological nanoparticles such as modified extracellular vesicles (EVs) that are likely to have lower toxicities have also been developed but face challenges in clinical translation as they have primarily been produced from cancerous cells/cell lines and have high batch-to-batch variability. To overcome these issues, herein, we demonstrate that EVs isolated from neutrophils may be loaded with a specific diagnostic agent (indocyanine green) in a facile manner within a few hours, that these agent-loaded EVs are retained <i>in vivo</i> in mouse tumors for longer with a ∼5-fold increase in retention when compared to free diagnostic agents and hence facilitate short-term longitudinal imaging of the tumor microenvironments. The use of an individual's own cell-derived EVs requiring minimal <i>ex vivo</i> manipulations increases the likelihood of translating such a system into the clinic.