Researchers have developed a new nanomaterial-based approach to enhance the ability of stem cells to deliver healthy mitochondria to stressed or damaged cells, according to a recent study published in the Proceedings of the National Academy of Sciences.
The study focused on engineering molybdenum disulfide (MoS₂) nanoflowers with atomic-scale modifications. These nanoflowers were used to treat human mesenchymal stem cells (hMSCs), turning them into what researchers call “mitochondrial biofactories.” The modified stem cells showed increased mitochondrial biogenesis, which means they produced more mitochondria and were better able to transfer these organelles to other cells under stress.
"Mitochondria are organelles found in most eukaryotic cells and are often referred to as the cell’s 'powerhouses.' They produce adenosine triphosphate (ATP) through cellular respiration, providing fuel for cellular activities. Mitochondria possess a double membrane and their own DNA (mtDNA)."
Proper function of mitochondria is essential for cell health because they provide energy and support key metabolic processes. When mitochondria malfunction, it can lead to diseases such as cardiovascular disease, neurodegenerative disorders, and inherited metabolic conditions.
Intercellular mitochondrial transfer—where one cell donates its mitochondria to another—has been identified as a process that may help repair damaged tissues. Mesenchymal stem cells are considered promising donor cells due to their accessibility and practical handling. However, their natural rate of mitochondrial transfer is limited.
"Intercellular mitochondrial transfer, particularly from mesenchymal stem cells (MSCs), has emerged as a key biological process in which cells exchange mitochondria to reduce stress and support tissue repair. This strategy may reduce the burden of mutant mtDNA by altering mtDNA content in recipient cells, while also restoring cellular respiration and survival by providing additional energy-generating components."
The MoS₂ nanoflowers created by researchers activate important regulators of mitochondrial biogenesis such as PGC-1α and TFAM. Their structure allows them to neutralize reactive oxygen species inside the cell, further stimulating genes involved in mitochondrial production. Compared with conventional small-molecule drugs—which can have short half-lives or toxic side effects—the nanoflower approach provided stronger stimulation of mitochondrial biogenesis without significant toxicity at tested concentrations.
"Researchers synthesized MoS₂ nanoflowers of varying sizes to investigate the impact of the surface area-to-volume ratio on cellular processes. By adjusting the molar ratio of molybdenum and sulfur precursors and modulating synthesis conditions between 120–200 °C for 6–18 hours, researchers obtained nanoflowers ranging from 50 to 250 nm."
The study found that smaller nanoparticles had improved uptake by hMSCs but both small and large particles effectively enhanced mitochondrial biogenesis when internalized by the stem cells.
"Researchers investigated whether MoS₂ nanoflowers could enhance mitochondrial biogenesis by activating the PGC-1α pathway, a central regulator of this process. Mechanistically, this pathway is triggered by sirtuins (SIRTs), with SIRT1 playing a dominant role, or by AMP-activated protein kinase (AMPK). The study provides stronger experimental support for an SIRT1-dependent mechanism than for AMPK involvement."
When these engineered hMSCs were co-cultured with smooth muscle cells under stress conditions—including exposure to drugs known to damage mitochondria—the recipient cells received more functional mitochondria via tunneling nanotubes. As a result, they showed increased ATP production and reduced oxidative stress.
"Experimental findings demonstrate that MitoFactory transfer increases energy production in recipient cells by boosting mitochondrial content. Further gene set enrichment analysis (GSEA) revealed that smooth muscle cells receiving these mitochondria had higher activity in pathways related to energy production and mitochondrial function."
In tests using cardiac fibroblasts exposed to doxorubicin—a chemotherapy drug known for causing heart damage—transfer of mitochondria from MoS₂-treated hMSCs helped restore normal function and reduced cell death rates.
Engineered hMSCs treated with MoS₂ nanoflowers represent an early-stage therapeutic platform that targets diseases caused by faulty mitochondria directly at their source rather than only managing symptoms. However, researchers caution that further studies are needed before clinical use: "However, further studies are needed to evaluate long-term safety, biodistribution, and immunogenicity before clinical translation."
This proof-of-concept highlights potential new directions for treating diseases linked with mitochondrial dysfunction but remains at an early stage pending further research.
