Abstract

Radiotherapy (RT) paradoxically promotes tumor metastasis by inducing inflammation, neutrophil recruitment, and the formation of neutrophil extracellular traps (NETs). A key mediator of this pro-metastatic process is CCDC25, a DNA sensor on tumor cells that recognizes NETs and triggers cytoskeletal remodeling. Here, we report a neutrophil-hijacking nanoplatform (OS-D) that delivers siRNA targeting CCDC25 and reprograms neutrophils toward an anti-tumor phenotype to inhibit NET-driven metastasis. OS-D is constructed by encapsulating CCDC25 siRNA into bacterial outer membrane vesicles (OMVs), further modified with pH-sensitive DSPE-PEOz for tumor-responsive release. OS-D selectively binds to neutrophils via pathogen-associated molecular patterns (PAMPs), leveraging neutrophil recruitment after RT for targeted delivery. Within the inflamed tumor microenvironment, OS-D-loaded neutrophils accumulate at tumor sites, where they release siRNA to silence CCDC25 in tumor cells, thereby disrupting NET-mediated metastatic signaling. Concurrently, activated neutrophils secrete cytotoxic and immunostimulatory factors, enhancing anti-tumor immunity. This strategy synergizes immune modulation with gene silencing to amplify RT efficacy and suppress metastasis, offering a safe and translatable approach to overcome RT-induced tumor progression.