image: Schematic overview of representative engineering strategies for mitochondrial delivery. After isolation from donor cells, functional mitochondria can be modified or packaged using distinct delivery platforms before transfer into recipient cells. Surface-engineered mitochondria are generated by coating isolated mitochondria with lipid-based or polymeric materials, such as dextran-TPP, to enhance mitochondrial uptake. Cell-mediated delivery exploits cellular carriers or engineered donor cells, such as mitochondria-transferred macrophages and Miro1-enhanced mesenchymal stem cells, to facilitate mitochondrial transport and transfer to injured or inflamed tissues. Vesicle-encapsulated delivery protects mitochondria within membrane-derived structures, including erythrocyte membrane-derived mitochondrial capsules, super mitochondria-enriched extracellular vesicles (Super-EV-Mito), and enucleated mesenchymal stem cell-derived microvesicles (Mito@euMVs). These engineering approaches aim to preserve mitochondrial integrity, improve delivery efficiency, and promote functional mitochondrial transfer into recipient cells.
Credit: ©Science Bulletin
Mitochondria are often known as the “powerhouses” of the cell. When they are damaged, cellular energy production declines, contributing to many diseases, including neurodegenerative disorders, cardiovascular and cerebrovascular diseases, inherited mitochondrial diseases, and aging-associated tissue degeneration. Mitochondrial transplantation, which aims to supply healthy mitochondria directly to damaged cells, has therefore emerged as a promising organelle-level therapeutic strategy. However, free mitochondria are fragile outside cells. They can rapidly lose activity and are often inefficiently delivered to diseased cells. A key challenge is therefore how to deliver functional mitochondria in a stable, efficient, and precise manner.
In a new Perspective article published in Science Bulletin, Yi Liu from the Joint School of Life Sciences, Guangzhou Medical University, and colleagues, summarize recent advances in engineered mitochondrial delivery. The article, entitled “Engineering mitochondrial delivery for efficient and precise mitochondrial transplantation,” proposes that mitochondrial transplantation should move beyond simple organelle supplementation toward a precise and standardizable organelle therapy.
The Perspective summarizes four major engineered mitochondrial delivery strategies. Surface-engineered mitochondria use lipid membranes or polymers to improve mitochondrial uptake, although protection against extracellular stress may remain limited. Cell-mediated mitochondrial delivery uses living cells, such as macrophages or mesenchymal stem cells, to transport mitochondria to injured or inflammatory tissues, but this approach requires better control of carrier-cell stability and mitochondrial release. Vesicle-encapsulated mitochondrial delivery packages mitochondria within membrane-derived vesicles, protecting them from extracellular damage and improving uptake. Representative systems include mesenchymal stem cell-derived microvesicles, super mitochondria-enriched extracellular vesicles, and erythrocyte membrane-derived mitochondrial capsules. Cell-type-specific mitochondrial targeting, such as the MitoCatch system, further aims to guide donor mitochondria into defined recipient cell populations in complex tissues such as the brain, retina, and heart.
The authors also emphasize that clinical translation will require standardized manufacturing, quality control, storage, delivery, biodistribution, safety and efficacy assessment, patient selection, and regulatory development. Key issues include mitochondrial source, isolation and purification, protective formulation, mitochondrial function, mitochondrial DNA integrity, dose normalization, storage stability, in vivo tracking, disease indication, and regulatory classification.
Together, these advances suggest that mitochondrial transplantation is entering a new stage. Its future success will depend not only on the mitochondrial cargo itself, but also on how mitochondria are engineered, protected, targeted, manufactured, evaluated, and regulated. Engineered mitochondrial delivery may help transform mitochondrial transplantation from an experimental intervention into a clinically testable precision organelle therapy.