As informed by the International Society for Cell & Gene Therapy, Mesenchymal Stromal/Stem Cells (MSCs) comprise of a cell population that includes mostly stromal cells that show secretory, immunomodulatory and homing properties, and a small fraction of mesenchymal stem cells that demonstrate stem-cell like properties such as self-renewal and differentiation (into osteocytes, adipocytes and chondrocytes), and express and lack a specific group of CD markers [1]. These cells are located in various body tissues [2], mainly near the blood vessels that are found in highly vascularized body tissues. Thus, these cells can be obtained from various sources, most commonly from the bone marrow, perinatal tissue and adipose tissue; the source determining the optimal mode of cell delivery under clinical settings [3]. Collectively, these cells are capable of self-regeneration, niche-dependent multilineage differentiation, migration towards injury/inflammation sites and secretion of immunomodulatory factors at the target site. Thus, MSCs show great reparative and therapeutic potential and are extremely valuable for cell-based therapy [2]. Accordingly, in the last decade, the number and types of MSC clinical applications have diversified immensely [3].

Due to their therapeutic potential, MSCs are indeed used in several clinical trials to attempt ameliorate pathological states, but there are no clinically approved therapies in many cases. This is due to several reasons including potential risks and side-effects associated with MSC transplantation, poor homing at the target site due to trapping within capillaries [4, 5], inclusion/exclusion criteria in clinical studies, unknown disease pathology, and economics [6]. In clinical trials where MSC products expressing highly procoagulant tissue factor (TF/CD142) were administered intravascularly, there were reports of mild-to-severe adverse reactions (mostly thromboembolic complications). Instant Blood-Mediated Inflammatory Reaction (IBMIR) is a sequence of innate immune reactions to the cell graft upon blood contact. This leads to complement and coagulation activation and subsequent effector cell engagement to sequester and destroy most of the administered MSCs due to their incompatibility with human blood. This compromises both the patient safety and the efficacy of therapeutic MSCs that are used as intravascular infusions [3, 7].

In addition, there are limitations and challenges in the methodologies deployed during the stages of MSC extraction/isolation, pre-transplantation cell preparation and post-transplantation cell detection. Notably, for successful MSC therapy, cells must be obtained in sufficient numbers from the source for in-vitro expansion, survive the stressful in-vitro cultivation steps, and upon administration, migrate to the target site, engraft, home, proliferate, and retain their differentiation ability and function in-vivo i.e. secrete appropriate trophic and immunomodulatory factors that heal the injury [8].

In context, the routinely encountered problems include low numbers of MSCs obtained from source, source-dependent variability in differentiation and proliferation potential, variability in the MSC isolation protocol, senescence during in vitro expansion, loss of differentiation and proliferation potential in-vitro, and the loss of MSC homing abilities. In addition to the risks of tumorigenicity, immunogenicity and toxicity [9], other issues related to post-transplantation stages include the presence of low numbers at target site, loss of transplanted cells, loss of detection signal, and diminished differentiation and reparative functionality in-vivo [5, 6, 10, 11].

Bearing the challenges posed by MSCs, this article briefly discusses the potential of using MSC-derived exosomes in clinical applications and the significance of iron-oxide nanoparticle (IONP)-tagged MSC exosomes in enhancing therapeutics. While MSC-derived exosomes offer advantages, the main advantages offered by IONP-tagged MSC exosomes are improved detection in vivo, improved organ targeting by employing magnets to guide the exosomes, and activation of signalling pathways in MSCs to release therapeutic factors from the cells, thereby adding to the MSC therapeutic efficacy.