Abstract
<title>Abstract</title> <p>Inducing oxidative stress-driven immunogenic regulated cell death (RCD) has emerged as a promising strategy in cancer therapy. Here, following KMnO4 oxidation, an ultrathin amorphous MnOx layer is conformally anchored on porous silicon nanoparticles (PSiNPs) via interfacial Si–O–Mn bonding, governed by the doping-dependent electronic properties of the silicon substrate. Beyond the surface MnOx overlayer (~4 nm), the Si–O–Mn interface provides sustained redox-active sites for glutathione (GSH) depletion via progressive decomposition. In addition, interfacial electron transfer through Si–O–Mn bonding further enhances the oxidation state of Mn centers, thereby facilitating GSH depletion. The exposed oxidized PSiNPs matrix exhibits superoxide dismutase-like activity, promoting the conversion of •O2− into H2O2 and ultimately enabling upstream amplification of intracellular reactive oxygen species cascades (•O2− → H2O2 → •OH). Consequently, this oxidative stress nanoamplifier effectively induces interconnected multimodal RCD and potentiates antitumor immunity across three tumor models, thereby enhancing the efficacy of immune checkpoint blockade therapy. Finally, given that the substantially reduced Mn loading (17.5 ± 3.6 wt%) minimizes Mn2+-associated systemic toxicity, the developed PSiNPs-based nanosystem with excellent biosafety demonstrates the important potential for inducing oxidative stress-driven immunogenic RCD in cancer therapy.</p>