Metabolic PANoptosis orchestrated by porous silkworm-like PtFeCoTeMn high-entropy nanozyme for synergistic cancer therapy.

Hepatocellular carcinoma therapy is limited by sorafenib (Sor) resistance, hypoxia, and elevated glutathione (GSH). Conventional nanozymes cannot simultaneously address these issues while reprogramming tumor metabolism. We synthesized uniform porous silkworm-like PtFeCoTeMn high-entropy nanorods (HENRs) with peroxidase-, nicotinamide adenine dinucleotide oxidase-, catalase-, and glutathione oxidase-like activities via one-pot co-reduction, coupled by loading them with glucose oxidase (GOx) and Sor. The PtFeCoTeMn HENRs-GOx/Sor generates reactive oxygen species while depleting glucose and GSH, triggering full PANoptosis in MHCC97H cells through apoptosis, pyroptosis, and necroptosis. In vivo studies achieve ∼90% tumor suppression with minimal toxicity, identified by cleaved caspase-3, GSDME-N, p-MLKL biomarkers. The high-entropy nanozyme-driven metabolic-PANoptosis mechanism orchestrates multiple therapeutic pathways beyond single-enzyme systems. This modular approach suggests universal applicability to other solid tumor requiring metabolic-immune reprogramming.