Nanoparticle Delivery of MnO2 and Anti-angiogenic Therapy to Overcome Hypoxia-Driven Tumor Escape and Suppress Hepatocellular Carcinoma

Anti-angiogenic therapy is widely administered in many cancers, and the anti-angiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, anti-angiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME), and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen, but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging (MRI) and drug release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of TAMs, promoting macrophage polarization toward the immunostimulatory M1 phenotype and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver anti-angiogenic agents, efficiently modulate the hypoxic TME and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.