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Updated: Jan 4, 2026
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Defeating relapsed and refractory malignancies through a nano-enabled mitochondria-mediated respiratory inhibition
Zhengyang Yang1, Jiafeng Wang1, Song Liu1
1Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan RD, Nanjing, 210008, China.
Abstract:
Hypoxia, which frequently reduces the sensitivity to many therapeutic interventions, including chemotherapy, radiotherapy and phototherapy, has been acknowledged as an important reason for poor prognosis. Burgeoning evidences have proved that the tumor hypoxia microenvironment can reduce the therapeutic effect on tumor through inhibiting the drug efficacy, limiting immune cell infiltration of tumors and accelerating tumor recurrence and metastasis. However, the relationship between oxygen supply and the proliferation of cancer cells is still ambiguous and argued. Different from the current commonly used oxygen supply strategies, this study concentrated on the reduction of endogenous oxygen consumption. Specifically, a novel photosensitizers (IR780) and metformin are packaged in PEG-PCL liposomes. Once such nanoparticles accumulated in tumor tissues, the tumor foci were irradiated through 808 nm laser, generated ROS to further release metformin and IR780. Metformin can directly inhibit the activity of complex Ⅰ in the mitochondrial electron transport chain, thus performed a potent inhibitor of cell respiration. After overcoming tumor hypoxia, the combination of mitochondria-targeted photodynamic therapy (PDT) and photothermic therapy (PTT) via IR780 may achieve superior synergistically therapeutic efficacy. Benefit from excellent characteristics of IR780, such synergistic PDT PTT with the inhibition of mitochondrial respiration can be monitored through near-infrared/photoacoustic dual-modal imaging. Such a conception of reducing endogenous oxygen consumption may offer a novel way to solve the important puzzles of hypoxia-induced tumor resistance to therapeutic interventions, not limited to phototherapy.
Insights
This study introduces a novel approach to combat tumor hypoxia by reducing endogenous oxygen consumption using IR780 and metformin nanoparticles. This strategy enhances cancer therapy efficacy and allows for dual-modal imaging monitoring.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Nanomedicine
Background:
- Tumor hypoxia is a major cause of poor prognosis and resistance to therapies like chemotherapy and radiotherapy.
- Hypoxia impairs drug efficacy, limits immune infiltration, and promotes tumor recurrence and metastasis.
- Current strategies focus on oxygen supply, but the relationship between oxygen and cancer cell proliferation remains debated.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting tumor hypoxia by reducing endogenous oxygen consumption.
- To investigate the synergistic effects of combining photodynamic/photothermic therapy with mitochondrial respiration inhibition.
- To enable monitoring of therapeutic efficacy using dual-modal imaging.
Main Methods:
- PEG-PCL liposomes encapsulating IR780 (photosensitizer) and metformin were developed.
- Nanoparticles were designed to accumulate in tumor tissues.
- 808 nm laser irradiation triggered ROS generation, releasing metformin and IR780 to inhibit mitochondrial respiration and induce synergistic therapy.
- Near-infrared/photoacoustic dual-modal imaging was used for monitoring.
Main Results:
- Metformin effectively inhibited mitochondrial complex I activity, reducing cellular respiration.
- The combination of IR780-mediated photodynamic/photothermic therapy with metformin overcame tumor hypoxia.
- Dual-modal imaging allowed for real-time monitoring of the synergistic therapeutic effects.
- The approach demonstrated potential for overcoming hypoxia-induced therapeutic resistance.
Conclusions:
- Reducing endogenous oxygen consumption is a viable strategy to address tumor hypoxia and enhance cancer therapy.
- The developed nanoparticle system offers synergistic therapeutic benefits through combined PDT, PTT, and mitochondrial respiration inhibition.
- This approach provides a novel platform for overcoming therapeutic resistance in various cancer treatments, monitorable via advanced imaging techniques.
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