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

BACKGROUND

The efficacy of radiotherapy (RT) is often compromised by tumor radioresistance and an immunosuppressive microenvironment. Two key limitations are the clearance of apoptotic cells (efferocytosis), which can promote an immunosuppressive phenotype, and the acidic tumor microenvironment (TME) that further restrains antitumor immunity. An ideal radiosensitizer should not only enhance radiation-induced cell death but also address these immunological barriers to unlock robust systemic antitumor immunity.

METHODS

We constructed a multifunctional nano-system based on mesoporous organosilicon (HMON) as a template. Leveraging the tunability of the -Si-O-Si- framework, we incorporated manganese (Mn) and calcium (Ca) elements to form a unique -Si-O-M- hybrid structure (M = Mn or Ca). This composite was subsequently loaded with Omeprazole sodium (PPI) and efferocytosis inhibitor, and the surface was modified with hyaluronic acid (HA) for active targeting. In vitro, the radiosensitizing mechanism was investigated in 4T1 cells via western blot, immunofluorescence and flow cytometry. In vivo efficacy was evaluated in 4T1 tumor-bearing BALB/c mice following combined nano-system and RT treatment.

RESULTS

The resulting nano-system exhibited a high T1 relaxivity (r1 = 8.95 mM⁻¹s⁻¹). In vitro and in vivo studies demonstrated that it significantly enhanced radiation-induced oxidative stress and mitochondrial dysfunction. The combination therapy achieved a remarkable ~ 96% tumor growth inhibition in 4T1 tumor-bearing mice. Crucially, it potentiated immunogenic cell death and activated the cGAS-STING pathway, evidenced by a > 3-fold increase in mature dendritic cells (DCs) and a > 4-fold enhancement in tumor-infiltrating cytotoxic T lymphocytes.

CONCLUSION

This study presents a novel "ion-interference amplifier" strategy that concurrently enhances radiosensitization and immune response, offering a powerful model for synergistic radio-immunotherapy. Meanwhile, the integration of MRI-based tracking further underscores its potential for clinical translation.