Emerging insights into mitochondria-specific targeting and drug delivering strategies: Recent milestones and therapeutic implications

Mitochondria are a major intracellular organelle for drug targeting due to its functional roles in cellular metabolism and cell signaling for proliferation and cell death. Mitochondria-targeted treatment strategy could be promising to improve the therapeutic efficacy of cancer while minimizing the adverse side effects. Over the last decades, several studies have explored and focused on mitochondrial functions, which has led to the emergence of mitochondria-specific therapies. Molecules in the mitochondria are considered to be prime targets, and a wide range of molecular strategies have been designed for targeting mitochondria compared with that of the cytosol. In this review, we focused on the molecular mechanisms of mitochondria-specific ligand targeting and selective drug action strategies for targeting mitochondria, including those premised on mitochondrial targeting of signal peptides (MTS), cell-penetrating peptides (CPPs), and use of lipophilic cations. Furthermore, most research has concentrated on specific conjugation of ligands to therapeutic molecules to enhance their effectiveness. There are several variations for the ideal design and development for mitochondrial-targeted drugs, such as selecting a suitable ligand and linker targets. However, some challenges related to drug solubility and selectivity could be resolved using the nanocarrier system. Nanoparticles yield excellent advantages for targeting and transmitting therapeutic drugs, and they offer elegant platforms for mitochondria-specific drug delivery. We explain many of the advanced and proven strategies for multifunctional mitochondria-specific targets, which should contribute to achieving better anticancer therapies in a promising future.