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Synergetic lethal energy depletion initiated by cancer cell membrane camouflaged nano-inhibitor for cancer therapy

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Abstract

Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer. Although strategies to impede mitochondrial energy supply have been rapidly developed, the anticancer efficacy is still far from satisfactory, mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we construct a cancer cell membrane camouflaged nano-inhibitor, mTPPa-Sy nanoparticle (NP), which co-encapsulates OXPHOS inhibitor (mitochondrial-targeting photosensitizers: TPPa) and glycolysis inhibitor (syrosingopine (Sy)) for synergistically blocking the two different energy pathways. The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells. Under laser irradiation, the mitochondrial-targeting TPPa, which is synthesized by conjugating pyropheophorbide a (PPa) with triphenylphosphin, produces excessive reactive oxygen species (ROS) and further disrupts the OXPHOS. Interestingly, OXPHOS inhibition reduces O2 consumption and improves ROS production, further constructing a closed-loop OXPHOS inhibition system. Moreover, TPPa-initiated OXPHOS inhibition in combination with the Sy-triggered glycolysis inhibition results in lethal energy depletion, significantly suppressing tumor growth even after a single treatment. Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion, providing a prospective strategy for efficient cancer therapy.

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Acknowledgements

This work was financially supported by National Natural Science Foundation of China (No. 81773656), Liaoning Revitalization Talents Program (No. XLYC1808017), Shenyang Youth Science and Technology Innovation Talents Program (No. RC190454), and National Postdoctoral Foundation of China (No. 2021M693868).

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  1. Fudan Dong and Qikun Jiang contributed equally to this work.

Authors and Affiliations

  1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Fudan Dong, Qikun Jiang, Lingxiao Li, Tian Liu, Shiyi Zuo, Lin Gao, Mengna Fang, Bingjun Sun, Cong Luo, Zhonggui He & Jin Sun

  2. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Yanlin Gao

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  1. Fudan Dong
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Correspondence to Zhonggui He or Jin Sun.

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Dong, F., Jiang, Q., Li, L. et al. Synergetic lethal energy depletion initiated by cancer cell membrane camouflaged nano-inhibitor for cancer therapy. Nano Res. 15, 3422–3433 (2022). https://doi.org/10.1007/s12274-021-3948-0

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