Genetically engineered Magnesium/Manganese nanoparticles for cancer radioimmunotherapy

Radiotherapy (RT) has great potential on activating antitumor immunity for combination therapy, yet this effect is limited by immunosuppressive tumor microenvironment (TME) and the potential toxicity in immune cells from high-dose radiation. Herein, we developed engineered nanoparticles (NPs) (CVs@MgMn) composed of genetically edited cellular vesicles (CVs), MnO₂ and MgCO₃ for enhanced radioimmunotherapy by remolding TME and activating the stimulator of the interferon genes (STING) pathway. In the TME, the efficiently enriched CVs@MgMn were decomposed to generate hydroxyl (‧OH) and oxygen (O₂) for radiosensitization. Subsequently, reduced Mn²⁺ activated the STING pathway to promote dendritic cell (DC) maturation, and the released Mg²⁺ boosted antitumor immunity by regulating CD8⁺ T cell metabolism and tumor-associated macrophage polarization. PD1-displayed CVs increased the targeting effect of NPs and mediated the PD-L1 blocking, all synergistically triggering antitumor immune responses. In both in situ and distant re-challenge models of melanoma, the combination of RT and nanocomposites demonstrated a strong radioimmunotherapy effect, resulting in an increased survival time and long-term immunological memory of tumor bearing mice. Moreover, MgCO₃ NPs synergistically promoted anti-PD-1 mAb immunotherapy. These findings highlight the importance of Mg/Mn combined supplementation and TME remolding during RT and immunotherapy, offered a simple and readily therapeutic strategy for patients with any type of solid tumor.