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Updated: Aug 28, 2025
Visualizing Mitophagy with Fluorescent Dyes for Mitochondria and Lysosome
Published on: November 30, 2022
Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death
Quanwei Sun1, Jinming Yang1, Wei Shen2
1School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230031, China.
Abstract:
Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO2 shell-coated multifunctional porphyrinic metal-organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H2O2. After entering tumor cells, the MnO2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O2-generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy, which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory, leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.
Insights
This study developed a novel metal-organic framework that enhances photodynamic therapy (PDT) by triggering pro-death autophagy and boosting anti-tumor immunity. This approach leads to tumor eradication and prevents recurrence by reprogramming cell death pathways.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Immunology
Background:
- Autophagy/mitophagy can hinder photodynamic therapy (PDT) by promoting tumor cell survival.
- However, excessive autophagy/mitophagy can induce immunogenic cell death and initiate anti-tumor immune responses.
Purpose of the Study:
- To develop a multifunctional nanoplatform that converts pro-survival autophagy/mitophagy to pro-death during PDT.
- To enhance anti-tumor immunity and therapeutic efficacy.
Main Methods:
- A MnO2 shell-coated porphyrinic metal-organic framework (MOF) loaded with CCCP was synthesized.
- The nanoplatform was designed to release CCCP in response to tumor microenvironment cues (GSH) and generate oxygen.
- The effect of CCCP-enhanced PDT on autophagy/mitophagy and anti-tumor immunity was evaluated in vitro and in vivo.
Main Results:
- The nanoplatform effectively delivered CCCP, enhanced PDT efficacy by depleting GSH and generating O2, and overcame tumor hypoxia.
- CCCP-induced mitochondrial uncoupling promoted excessive autophagy/mitophagy, leading to autophagic and immunogenic cell death.
- The treatment induced robust T-cell responses, immunological memory, complete primary tumor ablation, and prevented metastasis.
Conclusions:
- The strategy successfully repurposed autophagy/mitophagy from a pro-survival mechanism to a pro-death pathway, enhancing cancer therapy.
- This approach offers a versatile method for improving PDT efficacy through immunomodulation and controlled cell death induction.
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