Biodegradable MnO-Based Nanoparticles with Engineering Surface for Tumor Therapy: Simultaneous Fenton-Like Ion Delivery and Immune Activation

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.