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

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.