Near‐Infrared‐II Plasmonic Multi‐Enzyme Nanocapsules for Hyperthermia‐Augmented Cascade Catalytic Oncotherapy

Abstract Catalytic therapy based on artificial nanozymes holds considerable potential for cancer treatment but faces clinical challenges due to insufficient catalytic activity, limited enzymatic diversity, and the adaptive antioxidant tumor microenvironment. Herein, a near‐infrared II (NIR‐II) plasmonic multi‐enzyme capsule (PdCu‐pNS capsule) is developed to augment cascade catalytic therapy through hyperthermia synergy. The capsule structure integrates a NIR‐II plasmonic porous AuAg nanoshell (pNS) core with PdCu nanozymes, co‐encapsulated within a PEGylated silica nanocapsule. The PdCu‐pNS capsules exhibit distinct multi‐enzymatic activities, including peroxidase, catalase (CAT)‐, oxidase (OXD)‐, and glutathione peroxidase (GPx)‐like activities. Mechanistically, the CAT‐like activity sustains intratumoral O ₂ supply to alleviate hypoxia while synergistically promoting ^• O ₂ ˉ generation with the OXD‐like catalysis. Concurrently, the GPx‐mimetic activity depletes intracellular glutathione, thereby disrupting redox homeostasis in cancer cells. Notably, the NIR‐II plasmonic heating effects enhance enzymatic activities while enabling spatiotemporally controlled hyperthermia‐mediated tumor ablation. In vivo evaluations demonstrate exceptional therapeutic efficacy with an 87.7% tumor growth inhibition rate in 4T1 tumor‐bearing mice via the combinational catalytic‐hyperthermia therapy following intravenous administration of PdCu‐pNS capsules, Collectively, this work presents a multifunctional platform that synergizes multi‐enzyme cascades with plasmon resonance for improved therapeutic outcomes of catalytic therapy.