Sodium borohydride (NaBH₄) solution is a promising liquid “fuel” for continuous hydrogen supply through catalytic hydrolysis, offering a safer alternative to compressed hydrogen to fuel cells. However, the harsh thermal and chemical environments of concentrated NaBH₄ hydrolysis cause rapid catalyst deactivation. Herein, we synthesized a high-entropy layered hydroxide (HELH, FeCoNiCuZn@ZIF-67 (ZIF-67 = zeolitic imidazolate framework-67)) nanocatalyst via an in-situ etching-growth strategy with ZIF-67. The mechanical structure of residual ZIF-67 inside ensures the robustness of active centers and particles. The efficiency of hydrogen generation is guaranteed by the synergy of different metals in high-entropy structures, which involves borohydride adsorption and H₂ release. Benefiting from this cooperative architecture, the HELH catalyst achieves a high hydrogen generation rate of 8 L·min⁻¹·g⁻¹ in a 25 wt.% NaBH₄ solution. Density functional theory and electrochemical analyses reveal that abundant oxygen vacancies and multi-metal synergy optimize water activation and lower the reaction barrier. This work provides an effective strategy for designing robust high-entropy catalysts for extreme conditions.

To address monotherapy limitations in oncology, synergistic strategies are urgently needed to circumvent drug resistance and achieve favorable therapeutic outcomes. The development of new nanoformulations has emerged as one of the most promising approaches to resolve these challenges. In this study, we engineered an iRGD peptide-functionalized Fe single-atom nanozyme (FeSAN@iRGD) that integrates dual therapeutic modalities. The FeSAN@iRGD demonstrates exceptional peroxidase-like catalytic activity and achieves a remarkable 29.5% photothermal conversion efficiency under 808 nm laser irradiation, enabling effective synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT). Density functional theory calculations reveal that the atomically dispersed Fe-N₄ active sites facilitate efficient catalytic conversion of endogenous H₂O₂ into highly cytotoxic hydroxyl radicals in tumor microenvironment. The surface-conjugated iRGD peptide significantly enhances tumor-targeted accumulation. Both in vitro and in vivo evaluations confirm that the combined CDT/PTT approach synergistically enhances tumor cell apoptosis and suppresses tumor growth. Proteomic analysis comprehensively revealed reactive oxygen species (ROS)-mediated pathways including response to ROS, apoptosis, metabolic reprogramming, and cell cycle. This multifunctional nanozyme provides a promising paradigm for overcoming the therapeutic limitations of conventional cancer treatments through rational integration of catalytic nanomedicine and tumor-targeting strategies.