Natural Killer Cell‐Derived Extracellular Vesicles as Potential Anti‐Viral Nanomaterials

Abstract In viral infections, natural killer (NK) cells exhibit anti‐viral activity by inducing apoptosis in infected host cells and impeding viral replication through heightened cytokine release. Extracellular vesicles derived from NK cells (NK‐EVs) also contain the membrane composition, homing capabilities, and cargo that enable anti‐viral activity. These characteristics, and their biocompatibility and low immunogenicity, give NK‐EVs the potential to be a viable therapeutic platform. This study characterizes the size, EV‐specific protein expression, cell internalization, biocompatibility, and anti‐viral miRNA cargo to evaluate the anti‐viral properties of NK‐EVs. After 48 h of NK‐EV incubation in inflamed A549 lung epithelial cells, or conditions that mimic lung viral infections such as during COVID‐19, cells treated with NK‐EVs exhibit upregulated anti‐viral miRNA cargo (miR‐27a, miR‐27b, miR‐369‐3p, miR‐491‐5p) compared to the non‐treated controls and cells treated with control EVs derived from lung epithelial cells. Additionally, NK‐EVs effectively reduce expression of viral RNA and pro‐inflammatory cytokine (TNF‐α, IL‐8) levels in SARS‐CoV‐2 infected Vero E6 kidney epithelial cells and in infected mice without causing tissue damage while significantly decreasing pro‐inflammatory cytokine compared to non‐treated controls. Herein, this work elucidates the potential of NK‐EVs as safe, anti‐viral nanomaterials, offering a promising alternative to conventional NK cell and anti‐viral therapies.