Biodegradable MnO-Based Nanoparticles with Engineering Surface for Tumor Therapy: Simultaneous Fenton-Like Ion Delivery and Immune Activation
Zhaoli Sun, Zhiyi Wang, Tao Wang, Jingjing Wang, Hongtao Zhang, Ziyuan Li, Shuren Wang, Fugeng Sheng, Jing Yu, Yanglong Hou
Abstract
Immune checkpoint inhibitors have achieved significant clinical success but are still suffering from inadequate immune activation. It is worth noting that manganese as a nutritional inorganic trace element is closely associated with immune activation to fight against tumor growth and metastasis via the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. Herein, we designed hollow mesoporous silica-coated MnO nanoparticles (NPs), followed by conjugation of tumor homing peptide iRGD (CRGDKGPD). The obtained NPs (MnO@mSiO2-iRGD NPs) were applied to magnetic resonance imaging (MRI)-guided tumor immune-chemodynamic combination therapy, in which MnO NPs can be harnessed for cGAS-STING pathway-activated immunotherapy, Fenton-like reaction-induced reactive oxygen species upregulation, and T1-weighted MRI. The rough surface and large cavities of the mSiO2 shell promote cellular uptake and MnO NPs delivery. Meanwhile, it was found that MnO@mSiO2-iRGD NPs would dissociate under an acid environment, resulting in tumor specificity of MRI and exogenous Mn2+ release. Our results revealed that these pH-responsive biodegradable MnO@mSiO2-iRGD NPs synergized with α-PD-1 (PD-1 = programmed cell death-1) blocking antibody to highly elicit cytotoxic T lymphocyte infiltration and restrict melanoma progression and metastasis, which were envisioned as a promising candidate for tumor theranostics.