A Multifunctional Exosome with Dual Homeostasis Disruption\nAugments cGAS-STING-Mediated Tumor Immunotherapy by Boosting Ferroptosis

Ferroptosis\nhas shown great potential in activating antitumor immunity.\nHowever, the cunning tumor cells can evade ferroptosis by increasing\nthe efflux of iron and promoting the production of the reductant glutathione\nto mitigate oxidative stress. Herein, a multifunctional exosome loaded\nwith manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron\nmetabolism homeostasis and redox homeostasis to enhance tumor immunotherapy.\nThe efficient transport of MnIO by exosomes and the inhibition of\niron exocytosis by GW4869 led to a high retention of up to 29.57%\nID/g for iron in the tumors. Such a high retention of iron, in combination\nwith the BSO-induced disruption of the redox homeostasis, effectively\npromotes the ferroptosis of tumor cells. Consequently, the multifunctional\nexosomes that noticeably enhance ferroptosis by dual homeostasis disruption\nprovoke the cGAS-STING-based antitumor immune response and effectively\nsuppress tumor growth and lung metastasis in orthotopic breast cancer.