Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy

Area of Science:

• Mitochondrial biology and gene therapy
• Nanomedicine and drug delivery systems

Background:

• Mitochondrial DNA mutations cause severe disorders like neurodegenerative diseases and cancer.
• Current therapies for mitochondrial disorders are largely ineffective.
• Mitochondrial gene therapy offers a promising therapeutic avenue, necessitating efficient delivery systems.

Purpose of the Study:

• To design and compare novel polymer- and peptide-based systems for mitochondrial gene delivery.
• To evaluate the efficacy of these systems in targeting mitochondria, delivering genes, and enabling protein expression.
• To identify the most suitable system for advancing mitochondrial gene therapy towards clinical application.

Main Methods:

• Synthesis of a novel mitochondria-targeting polymer (polyethylenimine-dequalinium).
• Complexation of a mitochondrial-gene-based plasmid with polymer and peptide systems.
• Characterization of physicochemical properties (N/P ratio), cytotoxicity, cellular uptake, mitochondrial targeting (confocal microscopy), gene expression, and protein production.

Main Results:

• Polymeric complexes showed N/P-dependent physicochemical properties and cytotoxicity.
• Both polymer and peptide systems demonstrated successful mitochondrial targeting, gene delivery, and protein expression.
• Peptide systems exhibited superior performance, forming smaller, positively charged complexes at lower N/P ratios, leading to enhanced cellular transfection and mitochondrial gene delivery.

Conclusions:

• Peptide-based delivery systems are more effective than polymer-based systems for mitochondrial gene therapy.
• The findings support the development of peptide systems for clinical translation of mitochondrial gene therapy.
• This research significantly contributes to the implementation of mitochondrial gene therapy strategies.