Ion-interference amplifier nano-system enhances radiotherapy via mitochondrial dysfunction and efferocytosis...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Radiotherapy (RT) efficacy is limited by tumor radioresistance and an immunosuppressive tumor microenvironment (TME).
• Apoptotic cell clearance (efferocytosis) and TME acidity hinder antitumor immunity.
• An ideal radiosensitizer must enhance radiation-induced cell death and address immunological barriers.

Purpose of the Study:

• To develop a multifunctional nano-system for synergistic radio-immunotherapy.
• To enhance radiosensitization and overcome immune suppression in the tumor microenvironment.
• To investigate the nano-system's potential for MRI-based tracking and clinical translation.

Main Methods:

• Constructed a hybrid mesoporous organosilicon nano-system incorporating manganese/calcium, Omeprazole sodium (a proton pump inhibitor), and an efferocytosis inhibitor.
• Surface-modified the nano-system with hyaluronic acid for active targeting.
• Evaluated in vitro radiosensitizing mechanisms in 4T1 cells and in vivo efficacy in 4T1 tumor-bearing mice.

Main Results:

• The nano-system exhibited high T1 relaxivity for potential MRI tracking.
• Enhanced radiation-induced oxidative stress and mitochondrial dysfunction, leading to ~96% tumor growth inhibition.
• Potentiated immunogenic cell death, activated the cGAS-STING pathway, increased mature dendritic cells (>3-fold), and enhanced tumor-infiltrating cytotoxic T lymphocytes (>4-fold).

Conclusions:

• Introduced a novel "ion-interference amplifier" strategy for synergistic radio-immunotherapy.
• The nano-system concurrently enhances radiosensitization and immune response.
• Integrated MRI-based tracking highlights the potential for clinical translation.