Biodegradable Monometallic Manganese Nanoparticles for Multimodal Tumor Therapy

ABSTRACT Synergistic therapeutic nanoplatforms are of considerable interest in tumor therapy, but their translational potential is often limited by complex multicomponent designs and unknown in vivo degradation behavior. Herein, we show a degradable, single‐component manganese nanoparticles (Mn NPs) using liquid‐phase exfoliation of commercial bulk manganese powder for cancer therapy. In the acidic tumor environment, Mn NPs react with H + to generate Mn 2+ and H 2 and raise the local pH. The released Mn 2+ drives Fenton‐like reactions to produce ROS, while H 2 causes mitochondrial damage, which together lead to tumor cell death. In addition, Mn 2+ activates cGAS‐STING signaling and initiates antitumor immunity. Moreover, Mn NPs inhibit tumor growth in CT26, 4T1, and B16F10 mouse models and show better effects than Mn 2+ alone. Transcriptomic analysis further reveals activation of multiple immune‐related signaling pathways following Mn NP treatment. In a bilateral tumor model, unilateral injection of Mn NPs triggers a systemic antitumor immune response, leading to effective inhibition of distant, untreated tumor growth. Collectively, this study identifies Mn NPs as a simple, biodegradable, single‐component nanoplatform that offers a promising new route for multimodal tumor therapy.