Mitochondrial Targeting LNP
Introduction of Mitochondrial Targeting LNP
Mitochondrial malfunction has been linked to many disorders, including cancer, Alzheimer's, Parkinson's, and diabetes. The targeted delivery of an engineered gene or gene product to the mitochondrion is a critical first step in the therapeutic restoration of a lost cellular function. Mitochondrial targeting lipid-based nanoparticle (LNP) is a nanoparticle technology that delivers medicament or therapeutic material to the mitochondria of cells. The use of such systems entails extremely targeted delivery to cellular mitochondria, opening up new avenues for improving mitochondrial function and treating mitochondria-related illnesses. Features of mitochondrial targeting LNP include:
- Highly Selective
The Mitochondrial targeting LNP delivers to mitochondria with great selectivity, owing to its unique lipid structure.
- Biocompatibility
The Mitochondrial targeting LNP contains biocompatible lipids, lowering the risk of cytotoxicity and immunological responses.
- Efficient Delivery
The Mitochondrial targeting LNP can provide efficient drug delivery, ensuring that active components reach the mitochondria.
Application of Mitochondrial Targeting LNP
Mitochondrial targeting LNP is primarily used to successfully deliver medications or therapeutic substances into cell mitochondria for the treatment of mitochondrial diseases, antioxidant therapy, gene therapy, cancer treatment, and so on. MITO-Porter, a mitochondria-targeting LNP system, is surface-modified with a high concentration of octaarginine (R8), which cells can absorb via micropinocytosis. R8 can escape from macropinosomes into the cytosol, preventing lysosomal breakdown. MITO-Porter in the cytosol can connect to mitochondria by electrostatic interactions with R8. Encapsulated cargos are transported into the intra-mitochondrial compartment via membrane fusion. The following are two applications for MITO-Porter.
1. CoQ10-MITO-Porter
Coenzyme Q10 (CoQ10) is a well-known antioxidant that also serves as a coenzyme for ATP generation in mitochondria. A CoQ10-MITO-Porter is a mitochondrial targeting LNP with encapsulated CoQ10. Fig.1 indicates the antioxidant effect conferred by delivering coenzyme Q10 by targeting in vivo mitochondria.
Fig.1 A schematic representation of CoQ10 administration to mitochondria utilizing the MITO-Porter system.1
2. BBR- MITO-Porter
Berberine (BBR), a plant molecule, operates on the mitochondrial respiratory chain to cause a mitochondrial stress response, and its therapeutic activity is to modulate metabolic regulation. Fig 2 depicts a mitochondrial targeting LNP to deliver BBR into mitochondria efficiently, increasing the quantity of BBR that accumulates in mitochondria. The increase of BBR in mitochondria is critical for eliciting stronger pharmacological effects.
Fig.2 A schematic image depicting the mitochondrial delivery of BBR via the mitochondrial targeting LNP.2
Synthesis of Mitochondrial Targeting LNP
The synthesis of mitochondrial targeting LNPs involves liposome synthesis, surface modification, and nucleic acid packaging.
- LNP Synthesis
The first step in synthesizing LNPs is selecting the appropriate lipid component. This may include Ionizable lipids, helper lipids, cholesterol, and PEG-lipids to ensure the structure and stability of the LNP. They are mixed in a solvent so that they can self-assemble into nanoparticle structures.
- Surface Modification
For LNP to target mitochondria, specific molecules, often called targeting ligands, need to be introduced on its surface, such as Triphenylphosphonium (TPP), which is a mitochondria-targeting fragment that is coupled to phospholipids and assembled into mitochondria-targeted LNP. These ligands can selectively interact with molecules on the mitochondrial surface to achieve precise mitochondrial targeting.
- Nucleic acid Packaging
If mitochondrial targeting LNPs are utilized to transport oligos (such as siRNA or mRNA), they must be encapsulated within the lipid-based vector.
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References
- Yamada, Yuma, et al. "Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver." Journal of controlled release 213 (2015): 86-95.
- Hori, Ikuma, Hideyoshi Harashima, and Yuma Yamada. "Development of a Mitochondrial Targeting Lipid Nanoparticle Encapsulating Berberine." International Journal of Molecular Sciences 24.2 (2023): 903.
