Neutrophil-hijacking vesicles suppress NET-mediated metastasis via targeted siRNA delivery after radiotherapy

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Radiotherapy (RT) paradoxically enhances tumor metastasis through inflammation and neutrophil extracellular traps (NETs).
• CCDC25, a DNA sensor on tumor cells, mediates NET-driven metastasis by recognizing NETs and promoting cytoskeletal remodeling.

Purpose of the Study:

• To develop a neutrophil-hijacking nanoplatform (OS-D) for targeted delivery of CCDC25 siRNA.
• To reprogram neutrophils into an anti-tumor phenotype and inhibit RT-induced metastasis.

Main Methods:

• OS-D nanoplatform constructed using bacterial outer membrane vesicles (OMVs) encapsulating CCDC25 siRNA.
• OMVs modified with pH-sensitive DSPE-PEOz for tumor-responsive release.
• OS-D utilizes pathogen-associated molecular patterns (PAMPs) for selective neutrophil binding and RT-induced recruitment for targeted delivery.

Main Results:

• OS-D-loaded neutrophils accumulate at tumor sites, delivering siRNA to silence CCDC25 in tumor cells.
• Disruption of NET-mediated metastatic signaling and suppression of metastasis.
• Activated neutrophils secrete cytotoxic and immunostimulatory factors, enhancing anti-tumor immunity.

Conclusions:

• The OS-D nanoplatform effectively inhibits RT-induced metastasis by combining gene silencing with immune modulation.
• This strategy offers a safe and translatable approach to enhance RT efficacy and overcome tumor progression.