The transfer of mitochondria between cells has recently been revealed as a spontaneous way to protect the injured cells. However, the utilization of this natural transfer process for disease treatment is so far limited by its unsatisfactory transfer efficiency and selectivity. Here, we demonstrate that iron oxide nanoparticles (IONPs) can augment the intercellular mitochondrial transfer from human mesenchymal stem cells (hMSCs) selectively to diseased cells, owing to the enhanced formation of connexin 43-containing gap junctional channels triggered by ionized IONPs. In a mouse model of pulmonary fibrosis, the IONP-engineered hMSCs achieve a remarkable mitigation of fibrotic progression because of the promoted intercellular mitochondrial transfer, with no serious safety issues identified. The present study reports a potential method of using IONPs to enable hMSCs for efficient and safe transfer of mitochondria to diseased cells to restore mitochondrial bioenergetics.

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Background: Mesenchymal stem cells (MSCs) have been applied as a promising vehicle for tumour-targeted delivery of suicide genes in the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy against malignant gliomas. The efficiency of this strategy is largely dependent on the bystander effect, which relies on high suicide gene expression levels and efficient transportation of activated GCV towards glioma cells. However, up to now, the methods to enhance the bystander effect of this strategy in an efficient and safe way are still lacking and new approaches to improve this therapeutic strategy are required. Methods: In this study, MSCs were gene transfected using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs) to highly express HSV-tk. Both the suicide and bystander effects of HSV-tk expressed MSCs (MSCs-tk) were quantitatively evaluated. Connexin 43 (Cx43) expression by MSCs and glioma cells was measured under different treatments. Intercellular communication between MSCs and C6 glioma cells was examined using a dye transfer assay. Glioma tropism and the bio-distribution of MSCs-tk were observed. Anti-tumour activity was investigated in the orthotopic glioma of rats after intravenous administration of MSCs-tk followed by intraperitoneal injection of GCV. Results: Gene transfection using MFIONs achieved sufficient expression of HSV-tk and triggered Cx43 overexpression in MSCs. These Cx43 overexpressing MSCs promoted gap junction intercellular communication (GJIC) between MSCs and glioma cells, resulting in significantly inhibited growth of glioma through an improved bystander effect. Outstanding tumour targeting and significantly prolonged survival with decreased tumour size were observed after the treatment using MFION-transfected MSCs in glioma model rats. Conclusion: Our results show that iron oxide nanoparticles have the potential to improve the suicide gene expression levels of transfected MSCs, while promoting the GJIC formation between MSCs and tumour cells, which enhances the sensitivity of glioma cells to HSV-tk/GCV suicide gene therapy.

The inherent homing ability toward tumor sites of mesenchymal stem cells (MSCs) after systemic delivery has, during the past decade, created an impetus to develop these stem cells as living carriers for successful tumor-targeted therapy. Nevertheless, the controversies about the role of MSCs in promoting or inhibiting tumor progress are impeding the potential clinical application of this system, which is partly due to the contradictory immunomodulation capability. Therefore, in this review, updated progress in the applications of MSCs as the cellular carrier for tumor-targeting therapy, are summarized. In addition, the immunomodulating capability of MSCs and its influences on tumor progress and metastasis are highlighted. Finally, the advantages and potential risks of MSCs concerning their modulation of immune responses and the factors determining their immune properties are emphasized. It is hoped that the challenges surrounding the impacts on immune response induced by the administration of MSCs summarized in this review will provide a critical guidance for the rational design and proper application of MSCs-based targeting delivery system for tumor therapy.

Pulmonary inflammation is one of the most reported tissue inflammations in clinic. Successful suppression of inflammation is vital to prevent further inevitably fatal lung degeneration. Glucocorticoid hormone, such as methylprednisolone (MP), is the most applied strategy to control the inflammatory progression yet faces the challenge of systemic side effects caused by the requirement of large‐dosage and frequent administration. Highly efficient delivery of MP specifically targeted to inflammatory lung sites may overcome this challenge. Therefore, the present study develops an inflammation‐targeted biomimetic nanovehicle, which hybridizes the cell membrane of mesenchymal stem cell with liposome, named as MSCsome. This hybrid nanovehicle shows the ability of high targeting specificity toward inflamed lung cells, due to both the good lung endothelium penetration and the high uptake by inflamed lung cells. Consequently, a single‐dose administration of this MP‐loaded hybrid nanovehicle achieves a prominent treatment of lipopolysaccharide‐induced lung inflammation, and negligible treatment‐induced side effects are observed. The present study provides a powerful inflammation‐targeted nanovehicle using biomimetic strategy to solve the current challenges of targeted inflammation intervention.

Cationic polyethylenimine (PEI) is regarded as the “golden standard” of non-viral gene vectors. However, the superiority of PEI with high positive charge density also induces its major drawback of cytotoxicity, which restricts its application for an effective and safe gene delivery to stem cells. To redress this shortcoming, herein, a magnetic gene complex containing uniform iron oxide nanoparticles (UIONPs), plasmid DNA, and free PEI is prepared through electrostatic interactions for the gene delivery to bone marrow-derived mesenchymal stem cells (BM-MSCs). Results show that UIONPs dramatically promote the gene delivery to BM-MSCs using the assistance of magnetic force. In addition, decreasing the free PEI nitrogen to DNA phosphate (N/P) ratio from 10 to 6 has little adverse impact on the transgene expression levels (over 300 times than that of PEI alone at the N/P ratio of 6) and significantly reduces the cytotoxicity to BM-MSCs. Further investigations confirmed that the decrease of free PEI has little influence on the cellular uptake after applying external magnetic forces, but that the reduced positive charge density decreases the cytotoxicity. The present study demonstrates that the magnetic gene delivery not only contributes to the enhanced gene delivery efficiency but also helps to reduce required amount of PEI, providing a potential strategy for an efficient and safe gene delivery to stem cells.