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Engineering metal-non-metal asymmetric dual-atom catalyst for disulfidptosis-mediated potent immunotherapy
Guo-Dong Cheng1, Hua-Ying Hou2, Piao Suo1
1State Key Laboratory of Advanced Separation Membrane Materials, School of Material Science and Engineering & School of Chemistry, Tiangong University, Tianjin 300387, PR China.
Abstract:
Disulfidptosis, a novel form of immunogenic cell death triggered by intracellular disulfide stress, presents a promising avenue for cancer therapy. However, it is severely constrained by the low efficacy of disulfide homeostasis disruption. Herein, a powerful energy metabolism regulation strategy targeting nicotinamide adenine dinucleotide phosphate (NADPH) was proposed that leveraged a metal-non-metal (Co/Se) asymmetric dual-atom catalyst (DAC) to amplify disulfidptosis for potent immunotherapy. Experimental and theoretical analyses revealed that the asymmetric Co/Se pair altered the electronic structure with the upshifted d-band center of the Co active center, resulting in stronger substrate adsorption and charge transfer properties, endowing the DAC with stronger NADPH oxidase (NOx)-like activity to achieve a remarkable enhancement in NADPH depletion. After loading with the glycolysis inhibitor 3-bromopyruvic acid (3-BP) and capping with hyaluronic acid (HA), the obtained Co/Se DAC-3-BP@HA efficiently targeted tumor cells. Co/Se DAC and 3-BP were liberated upon internalization, reversing the energy metabolism pathway and catalyzing the depletion of NADPH, causing severe disulfide stress. This further induced the co-activation of apoptosis and disulfidptosis, showing a 93% suppression of primary tumor growth in vivo. More importantly, the disulfidptosis-mediated therapy robustly triggered an immune response, as evidenced by the maturation of dendritic cells and the phenotype transformation of tumor-associated macrophages from M2 to M1, ultimately resulting in significant inhibition of distant tumor growth and pulmonary metastasis. This work not only provides a novel strategy to initiate potent disulfidptosis-mediated immunotherapy using asymmetric DAC, but also establishes a general paradigm for targeting energy metabolism to enhance immunotherapeutic effect.
Insights
This study introduces a novel cancer therapy using a dual-atom catalyst to amplify disulfidptosis, a cell death pathway, by depleting nicotinamide adenine dinucleotide phosphate (NADPH). This approach enhances immunotherapy and significantly suppresses tumor growth.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Immunotherapy
Background:
- Disulfidptosis is a novel immunogenic cell death pathway triggered by disulfide stress, offering cancer treatment potential.
- Current disulfidptosis therapies are limited by low efficacy in disrupting disulfide homeostasis.
Purpose of the Study:
- To develop an energy metabolism regulation strategy targeting nicotinamide adenine dinucleotide phosphate (NADPH) depletion to enhance disulfidptosis for cancer immunotherapy.
- To investigate the efficacy of a metal-non-metal (Co/Se) asymmetric dual-atom catalyst (DAC) loaded with 3-bromopyruvic acid (3-BP) and hyaluronic acid (HA) for targeted cancer treatment.
Main Methods:
- Designed and synthesized a Co/Se asymmetric dual-atom catalyst (DAC) with enhanced NADPH oxidase-like activity.
- Loaded the DAC with glycolysis inhibitor 3-bromopyruvic acid (3-BP) and capped with hyaluronic acid (HA) for tumor cell targeting.
- Evaluated the in vivo efficacy in suppressing primary and distant tumor growth and metastasis, alongside immune response analysis.
Main Results:
- The Co/Se DAC demonstrated enhanced NADPH depletion activity due to altered electronic structure and stronger substrate adsorption.
- The Co/Se DAC-3-BP@HA formulation effectively targeted tumor cells, reversed energy metabolism, and induced severe disulfide stress, leading to apoptosis and disulfidptosis.
- Achieved 93% suppression of primary tumor growth and significant inhibition of distant tumor growth and pulmonary metastasis.
- Therapy robustly triggered an immune response, including dendritic cell maturation and M2 to M1 macrophage phenotype transformation.
Conclusions:
- Asymmetric dual-atom catalysts offer a novel strategy to initiate potent disulfidptosis-mediated immunotherapy by targeting energy metabolism.
- This approach establishes a general paradigm for enhancing immunotherapeutic effects through precise energy metabolism regulation.
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