Genetically engineered Magnesium/Manganese nanoparticles for cancer radioimmunotherapy

Area of Science:

• Biomedical Engineering
• Immunotherapy
• Nanotechnology

Background:

• Radiotherapy (RT) shows promise for activating antitumor immunity but is limited by the immunosuppressive tumor microenvironment (TME) and radiation toxicity.
• Existing combination therapies face challenges in overcoming TME-induced immunosuppression and off-target effects.

Purpose of the Study:

• To develop engineered nanoparticles (CVs@MgMn) for enhanced radioimmunotherapy.
• To investigate the synergistic effects of nanoparticles, RT, and immunotherapy in remodeling the TME and activating anti-tumor immune responses.

Main Methods:

• Genetically edited cellular vesicles (CVs) combined with MnO2 and MgCO3 were engineered into nanoparticles (CVs@MgMn).
• The nanoparticles were designed to decompose in the TME, generating reactive oxygen species for radiosensitization.
• The nanoparticles were investigated for their ability to activate the stimulator of the interferon genes (STING) pathway and modulate immune cell function.

Main Results:

• CVs@MgMn nanoparticles enhanced radiosensitization through hydroxyl and oxygen generation.
• Reduced Mn2+ activated the STING pathway, promoting dendritic cell maturation.
• Released Mg2+ modulated CD8+ T cell metabolism and tumor-associated macrophage polarization, boosting antitumor immunity.
• PD1-displayed CVs enhanced nanoparticle targeting and PD-L1 blockade, synergistically triggering immune responses.
• Combination therapy significantly increased survival and induced long-term immunological memory in melanoma models.
• MgCO3 nanoparticles synergistically enhanced anti-PD-1 antibody immunotherapy.

Conclusions:

• Engineered nanoparticles (CVs@MgMn) offer a promising strategy for enhanced radioimmunotherapy by remodeling the TME and activating the STING pathway.
• The combination of RT with these nanoparticles, along with immunotherapy, demonstrates significant therapeutic potential for solid tumors.
• This approach highlights the importance of magnesium/manganese supplementation and TME modulation in RT and immunotherapy.