Multifunctional biohybrid nanoplatform interferes electron transport chain amplifying mitochondrial...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Mitochondrial Biology

Background:

• Mitochondria and their electron transport chain (ETC) are vital in cancer progression.
• Targeting single ETC complexes has limited efficacy for inducing mitochondrial dysfunction.
• Developing multifunctional platforms is crucial for enhanced anti-cancer strategies.

Purpose of the Study:

• To synthesize a multifunctional nanoplatform (CMP-MOF@TK) for inducing mitochondrial dysfunction and enhancing anti-tumor immunity.
• To investigate the simultaneous inhibition of ETC complex I and IV using Zinc (Zn²⁺) and Fenofibric acid (FFa).
• To evaluate the platform's ability to trigger immunogenic cell death (ICD) and activate anti-tumor immune responses.

Main Methods:

• Synthesis of a multifunctional MOF@TK nanoplatform using Zn²⁺ and FFa.
• Modification of the nanoplatform with tumor cell membranes transfected with PD-1 (CMP-MOF@TK).
• Assessment of mitochondriotropic uptake, ROS-responsive drug release, ETC complex inhibition, ROS generation, ATP production, ICD induction, and anti-tumor immune activation.

Main Results:

• CMP-MOF@TK effectively induced mitochondrial dysfunction by synchronously inhibiting ETC complex I and IV.
• The platform promoted ROS generation, oxidative stress, and mitochondrial depolarization, leading to decreased ATP production.
• Mitochondrial damage mediated immunogenic cell death (ICD), increasing HMGB1 and CRT, while PD-1 transfection activated anti-tumor immunity.

Conclusions:

• The CMP-MOF@TK nano-biohybrid platform offers a potent strategy for cancer therapy by inducing mitochondrial dysfunction and enhancing anti-tumor immunity.
• Simultaneous inhibition of multiple ETC complexes presents a promising approach for cancer treatment.
• This work provides translational promise for developing novel anti-cancer therapies based on mitochondrial metabolism interference.