A Gas Nanobomb to Promote Drug Penetration and Amplify TACE Therapy for Orthotopic Liver Tumor

The worsening hypoxia, acidity, immunosuppression, and low drug penetration created by arterial embolization significantly limit the therapeutic efficiency of transarterial chemoembolization (TACE) therapy. To overcome these problems, nanoscale magnesium hydride (MgH₂) gas bombs are synthesized and then are co-dispersed with tirapazamine (TPZ) into lipiodol (Lip) to obtain an L-MgH₂&TPZ suspension, in which the MgH₂ nanobombs efficiently modulate the worsened tumor microenvironment (TME), reversed immunosuppression, promoted drug penetration, and amplified TACE therapy. After being injected into mouse tumors, MgH₂ nanobombs react with water to effectively generate OH^- to neutralize the acidic TME and reverse immunosuppression; hydrogen (H₂) gas bubbles enhance TPZ penetration and achieve hydrogen-based chemotherapy; and Mg²⁺ synergistically regulates T-cell function, resulting in significant inhibition for tumor growth. Moreover, the immunological effects of H₂ and Mg²⁺-induced antitumor immune responses further inhibit tumor growth and metastasis after combination with an immune checkpoint inhibitor. As demonstrated in the orthotopic rat liver cancer model, transarterial embolization of the L-MgH₂&TPZ suspension offers greatly enhanced therapeutic outcomes, and all of tumors are eradicated after 3 weeks of treatment, further confirming that the introduction of the MgH₂ nanobombs significantly modulates the acidic/immunosuppressive TME and promotes the penetration of TPZ to improve the efficacy of TACE therapy.