Key Takeaways & Executive Findings
- •• • Photothermal conversion efficiency reaches 55.6%, enabling effective NIR-induced hyperthermia at low laser power densities, which reduces off-target thermal damage to healthy tissues. • • The nanozyme exhibits five enzyme-like activities (CAT, OXD, POD, GPx, NOX), generating a cascade of ROS and depleting NADH, which impairs mitochondrial function and downregulates HSP70, overcoming tumor thermoresistance. • • In vivo biocompatibility at 400 ppm shows no hemolysis and no significant organ pathology or hematological fluctuations (Mon, RBC, HGB, HCT, MCV, MCH, MCHC, RDW-CV, RDW-SD, PLT, MPV, PDW), supporting safe systemic administration. • • The one-step synthesis method simplifies production and enhances heterostructure formation, increasing catalytic active sites and electron transfer, which is scalable for industrial manufacturing.
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Abstract
Photothermal therapy (PTT) is limited by heat shock protein (HSP) upregulation and mitochondrial-encoded thermoresistance in tumor cells. This study reports PtRhMo/Rh multi-metal nanozymes synthesized via a one-step method for cascade enzymatic therapy and enhanced PTT. The nanozymes exhibit a photothermal conversion efficiency of 55.6% and multiple enzyme-like activities: catalase (CAT), oxidase (OXD), peroxidase (POD), glutathione peroxidase (GPx), and NADH oxidase (NOX). These activities generate reactive oxygen species (ROS) and deplete NADH, disrupting the electron transport chain (ETC) and causing mitochondrial damage. This downregulates HSP70, sensitizing tumors to heat. In vivo biocompatibility tests at 400 ppm showed no hemolysis and no significant pathological changes in major organs. Hematological parameters remained stable. The synergistic approach directly kills tumor cells and weakens thermoresistance, offering a promising strategy for clinical translation.
1. Introduction
Conventional cancer treatments face limitations such as invasiveness and systemic toxicity. Near-infrared (NIR)-induced photothermal therapy (PTT) offers high penetration and non-invasive tumor ablation, but its efficacy is compromised by tumor thermoresistance. Upregulation of heat shock proteins (HSPs) and mitochondrial-encoded genes in the tumor microenvironment (TME) enhances heat resistance, reducing PTT effectiveness. Noble metal-based nanozymes can modulate ROS and reverse hypoxia, but single-metal systems suffer from low catalytic activity and limited functionality.
This study addresses these bottlenecks by designing PtRhMo/Rh multi-metal nanozymes via a one-step synthesis. The heterostructure integrates multiple enzymatic activities (CAT, OXD, POD, GPx, NOX) to amplify ROS generation and deplete NADH, disrupting the electron transport chain (ETC) and causing mitochondrial damage. This dual action downregulates HSP70 and sensitizes tumors to heat, significantly enhancing PTT. The nanozymes also exhibit high biocompatibility, with no hemolysis at 400 ppm and no organ toxicity, providing a viable strategy for clinical translation.
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LI Danyang, HA Enna, ZHU Yaoyao, HE Shuqing, KUANG Shaolong, HU Junqing (2025). One-step synthesis of PtRhMo/Rh nanozymes for mitochondrial damage-mediated photothermal/enzymatic therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-024-3300-6
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Frequently Asked Questions
What is the photothermal conversion efficiency of PtRhMo/Rh nanozymes, and how does it compare to existing photothermal agents?
The PtRhMo/Rh nanozymes achieve a photothermal conversion efficiency of 55.6%, which is competitive with gold-based nanoshells (~50%) and higher than many organic photothermal agents (<40%). This efficiency enables effective tumor ablation at lower laser power densities, reducing collateral damage to healthy tissues.
How does the nanozyme overcome tumor thermoresistance, and what specific molecular pathways are involved?
The nanozyme generates ROS via CAT, OXD, POD, and GPx-like activities and depletes NADH through NOX-like activity. This disrupts the electron transport chain (ETC), leading to mitochondrial damage and downregulation of HSP70. The reduction in HSP70 weakens the tumor's heat resistance, enhancing PTT efficacy.
What are the biocompatibility and safety profiles of PtRhMo/Rh nanozymes in vivo?
At concentrations up to 400 ppm, no significant hemolysis was observed. Histological analysis of major organs (heart, liver, spleen, lungs, kidneys) showed no inflammation or necrosis. Hematological parameters (Mon, RBC, HGB, HCT, MCV, MCH, MCHC, RDW-CV, RDW-SD, PLT, MPV, PDW) remained stable, indicating favorable biocompatibility.
What are the scalability and cost considerations for the one-step synthesis of PtRhMo/Rh nanozymes?
The one-step synthesis simplifies production by reducing processing steps and enabling heterostructure formation. While noble metals (Pt, Rh) are costly, the method minimizes waste and allows for high-yield production. Further optimization could reduce metal loading without compromising activity, improving cost-effectiveness for clinical translation.
How does the heterostructure enhance catalytic activity compared to single-metal nanozymes?
The heterostructure increases exposure of catalytic active sites and facilitates electron transfer due to localized surface plasmon resonance (LSPR) effects. This cascade amplification boosts ROS generation and NADH depletion, resulting in superior enzymatic therapy compared to single-metal counterparts.
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