Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy

Abstract

Background The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process. Methods In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn2+) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO2) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH4HCO3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively. Results In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO2. Moreover, the release of Mn2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H2O2) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively. Conclusions This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.

Design of manganese-based nanomaterials for pharmaceutical and biomedical applications

“…Furthermore, various biosensors have also been designed using Mn-NSs. [2][3][4] In general, Mn is a part of the Earth's chemical composition and is the twelfth most abundant element. Manganese oxide is the most common form of Mn, and present in a broad range of environmental flora and fauna to control the biogeochemical elemental cycle.…”

Gas-Amplified Metalloimmunotherapy with Dual Activation of Pyroptosis and the STING Pathway for Remodeling the Immunosuppressive Cervical Cancer Microenvironment

“…Activation of the cGAS-STING pathway can activate TIDCs, enabling them to effectively present tumor antigens and anti-inflammatory substances released during pyroptosis to T cells. , Therefore, simultaneous activation of the cGAS-STING pathway while inducing pyroptosis is expected to fully activate the immune pathway and amplify the adaptive immune response induced by pyroptosis. Among various cGAS-STING agonists, Mn 2+ has been shown to activate cGAS-STING signaling even in the absence of double-stranded DNA, thereby stimulating DC maturation . Consequently, Mn 2+ can be considered a propellant of the immune response to calcium overload mediated pyroptosis.…”

“…Among various cGAS-STING agonists, Mn 2+ has been shown to activate cGAS-STING signaling even in the absence of double-stranded DNA, thereby stimulating DC maturation. 27 Consequently, Mn 2+ can be considered a propellant of the immune response to calcium overload mediated pyroptosis. Moreover, H 2 Senhanced calcium pyroptosis can further amplify cGAS-STING activation by releasing mitochondrial DNA (mtDNA) as an adjuvant.…”

Smart responsive Fe/Mn nanovaccine triggers liver cancer immunotherapy via pyroptosis and pyroptosis-boosted cGAS-STING activation

“…Interestingly, pyroptosis is often accompanied by DNA damage, [ 7 , 9 ] including the production of double-stranded DNA (dsDNA). dsDNA can be detected by the cytoplasmic cGAS enzyme, leading to the conversion of adenylate triphosphate and guanosine triphosphate into 2’,3’-cyclic GMP-AMP and ultimately activating STING, resulting in the generation of type I interferons (especially IFN-β) and promoting the maturation of DCs [ 16 – 19 ]. Sun et al confirmed that Mn 2+ induces a hyperactivation of the cGAS-STING pathway, significantly enhancing the sensitivity of the cGAS enzyme to dsDNA [ 20 ].…”