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Published on: July 13, 2018
Protective Effect of Mitochondria-Targeted Polydopamine Nanoparticles in Alleviating Hepatic Ischemia-Reperfusion
Yihui Huang1, Xiao Cui1, Jian You1
1Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Hepatobiliary Diseases Society, Wuhan 430071, China.
Abstract:
Hepatic ischemia-reperfusion injury (IRI), driven primarily by excessive mitochondrial reactive oxygen species (ROS) generation, is a major cause of liver dysfunction, graft failure, and postoperative complications. However, no pharmacological agents have been clinically approved for its prevention or treatment, and there is an urgent need for effective therapeutic strategies. In this study, we established a nanoplatform composed of PEGylated polydopamine nanoparticles modified with the mitochondrial-targeting peptide SS-31 (PPS NPs). SS-31 peptide modification confers PPS NPs with efficient mitochondrial-targeting capability, thereby restoring mitochondrial membrane potential and reducing ROS accumulation in the hypoxia/reoxygenation model. Furthermore, treatment with PPS NPs significantly mitigates liver injury, decreases inflammatory factor levels, and inhibits neutrophil recruitment in mice subjected to IRI. Transcriptome sequencing and metabolomics analyses indicate that PPS NPs can protect the liver from ischemia-reperfusion injury by preserving mitochondrial integrity, reducing ROS generation, and regulating arachidonic acid and glutathione metabolism. By preserving mitochondrial function, maintaining cellular redox homeostasis, and suppressing inflammatory cascades, PPS NPs ultimately inhibit mitochondria-dependent apoptosis and confer protection against liver IRI, providing a practical therapeutic strategy for hepatic IRI clinical management.
Insights
A novel nanoplatform (PPS NPs) targets mitochondria to reduce reactive oxygen species (ROS) and prevent liver injury from ischemia-reperfusion (IRI). This strategy offers a promising therapeutic approach for hepatic IRI.
Area of Science:
- Biomedical Engineering
- Hepatology
- Nanomedicine
Background:
- Hepatic ischemia-reperfusion injury (IRI) causes significant liver dysfunction and graft failure.
- Current therapeutic options for hepatic IRI are limited, highlighting the need for novel treatments.
- Excessive mitochondrial reactive oxygen species (ROS) generation is a key driver of IRI pathogenesis.
Purpose of the Study:
- To develop and evaluate a nanoplatform for targeted delivery to mitochondria to mitigate hepatic IRI.
- To investigate the protective mechanisms of the nanoplatform against IRI-induced liver damage.
Main Methods:
- A nanoplatform (PPS NPs) was engineered using PEGylated polydopamine nanoparticles functionalized with the SS-31 peptide for mitochondrial targeting.
- In vitro studies assessed mitochondrial membrane potential and ROS accumulation under hypoxia/reoxygenation.
- In vivo studies utilized a mouse model of hepatic IRI to evaluate the therapeutic efficacy of PPS NPs, including inflammatory markers and neutrophil infiltration.
- Transcriptome sequencing and metabolomics analyses were performed to elucidate the underlying protective mechanisms.
Main Results:
- PPS NPs demonstrated efficient mitochondrial targeting, restoring membrane potential and reducing ROS accumulation.
- Treatment with PPS NPs significantly attenuated liver injury, reduced inflammatory factors, and inhibited neutrophil recruitment in IRI mice.
- Omics analyses revealed that PPS NPs protect the liver by preserving mitochondrial integrity, reducing ROS, and modulating arachidonic acid and glutathione metabolism.
Conclusions:
- The developed PPS NPs effectively protect against hepatic IRI by targeting mitochondria and restoring cellular homeostasis.
- This nanoplatform offers a promising therapeutic strategy for managing liver injury associated with IRI.
- The findings provide a foundation for further clinical development of targeted nanomedicines for hepatic IRI.
