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

High oxidative stress plays a significant role in activating intracellular signaling 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 immunosuppressive tumor microenvironment. Herein, the GSH/pH-sensitive Mn2+/polydopamine-incorporated hollow mesoporous tetrasulfide-bridged organosilica nanoreactors loaded with l-arginine (l-Arg) were successfully constructed (A@MnHMONs-PEG). Under near-infrared light (NIR) illumination, the programmed nanoreactors directly generate a large amount of ROS via "Mn2+-based Fenton-like catalysis and tetrasulfide bridge-mediated GSH depletion" for photothermal-intensified chemodynamic therapy, meanwhile ROS could oxidize the guanidine groups of l-Arg to produce nitric oxide (NO) for gas therapy. Moreover, both photothermal and massive ROS substantially 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 reverse immunosuppression and enhance immune response. In vivo experiments conclusively prove that our programmed nanoreactors could combine photothermal-chemodynamic-NO therapy and concurrently enhance immune response via ROS cascade amplification along with ONOO– storm for elimination of the primary tumor and inhibition of recurrence/metastasis. Our programmed nanoreactors open up new paths for improving the anticancer immune response.