Ultrasound-induced cascade nanozyme catalysis for enhanced tumor cell pyroptosis and systemic anti-tumor immunity

High levels of reactive oxygen species (ROS) are critical for inducing efficient pyroptosis. However, conventional sonosensitizers often exhibit limited ROS generation capacity, thereby restricting their pyroptotic efficacy. Herein, we report a PEGylated Fe/Co co-doped MoS₂ nanozyme (FeCo-MoS₂) as an advanced sonosensitizer. The incorporation of Fe and Co dopants optimizes the electronic structure of MoS₂ and increases the density of active sites. Under ultrasound (US) stimulation, FeCo-MoS₂ exhibits multi-enzyme mimetic activities, enabling efficient catalysis of endogenous hydrogen peroxide (H₂O₂) into ROS while simultaneously depleting glutathione (GSH). This dual action disrupts intracellular redox homeostasis within the tumor microenvironment, leading to pronounced mitochondrial oxidative stress. In turn, this activates the caspase-1/GSDMD signaling pathway, culminating in controlled pyroptotic cell death. In vitro, FeCo-MoS₂ combined with US treatment markedly induced cell membrane pore formation and elevated release of IL-18 and lactate dehydrogenase (LDH). In vivo studies demonstrated that this system not only suppressed primary and distant tumor growth and prevented lung metastasis, but also triggered the release of damage-associated molecular patterns (DAMPs). This promoted dendritic cell (DC) maturation and enhanced CD8⁺T cell infiltration, thereby eliciting a robust and durable anti-tumor immune response. Collectively, our findings highlight a strategy to potentiate pyroptosis and amplify systemic antitumor immunity, offering new insights into nanozyme-enhanced sonodynamic immunotherapy.