Programmed Nanoreactors Boost Immune Response through ROS Cascade Amplification along with RNS Storm

Highoxidative stress plays a significant role in activatingintracellularsignaling pathways that govern immunogenic cell death (ICD). Nevertheless,immune response is often confined by limited reactive oxygen species(ROS) production, upregulated antioxidant defense, and an immunosuppressivetumor microenvironment. Herein, the GSH/pH-sensitive Mn2+/polydopamine-incorporated hollow mesoporous tetrasulfide-bridgedorganosilica nanoreactors loaded with l-arginine (l-Arg) were successfully constructed (A@MnHMONs-PEG). Under near-infraredlight (NIR) illumination, the programmed nanoreactors directly generatea large amount of ROS via "Mn2+-based Fenton-likecatalysis and tetrasulfide bridge-mediated GSH depletion" forphotothermal-intensified chemodynamic therapy, meanwhile ROS couldoxidize the guanidine groups of l-Arg to produce nitric oxide(NO) for gas therapy. Moreover, both photothermal and massive ROSsubstantially induce cancer immune responses by up-regulating ICD.Furthermore, the more powerful peroxynitrite anion (ONOO-) is sequentially generated through the interaction of ROS and NO.It could polarize macrophages from M2 into M1 phenotype to reverseimmunosuppression and enhance immune response. In vivo experiments conclusively prove that our programmed nanoreactorscould combine photothermal-chemodynamic-NO therapy and concurrentlyenhance immune response via ROS cascade amplification along with ONOO- storm for elimination of the primary tumor and inhibitionof recurrence/metastasis. Our programmed nanoreactors open up newpaths for improving the anticancer immune response.