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Mesenchymal stem cells (MSCs) are considered a promising regenerative therapy due to their ability to migrate toward damaged tissues. The homing ability of MSCs is unique compared with that of non-migrating cells and MSCs are considered promising therapeutic vectors for targeting major cells in many pathophysiological sites. MSCs have many advantages in the treatment of malignant diseases, particularly rheumatoid arthritis (RA). RA is a representative autoimmune disease that primarily affects joints, and secreted chemokines in the joints are well recognized by MSCs following their migration to the joints. Furthermore, MSCs can regulate the inflammatory process and repair damaged cells in the joints. However, the functionality and migration ability of MSCs injected in vivo still show insufficient. The targeting ability and migration efficiency of MSCs can be enhanced by genetic engineering or modification, eg, overexpressing chemokine receptors or migration-related genes, thus maximizing their therapeutic effect. However, there are concerns about genetic changes due to the increased probability of oncogenesis resulting from genome integration of the viral vector, and thus, clinical application is limited. Furthermore, it is suspected that administering MSCs can promote tumor growth and metastasis in xenograft and orthotopic models. For this reason, MSC mimicking nanoencapsulations are an alternative strategy that does not involve using MSCs or bioengineered MSCs. MSC mimicking nanoencapsulations consist of MSC membrane-coated nanoparticles, MSC-derived exosomes and artificial ectosomes, and MSC membrane-fused liposomes with natural or genetically engineered MSC membranes. MSC mimicking nanoencapsulations not only retain the targeting ability of MSCs but also have many advantages in terms of targeted drug delivery. Specifically, MSC mimicking nanoencapsulations are capable of encapsulating drugs with various components, including chemotherapeutic agents, nucleic acids, and proteins. Furthermore, there are fewer concerns over safety issues on MSC mimicking nanoencapsulations associated with mutagenesis even when using genetically engineered MSCs, because MSC mimicking nanoencapsulations use only the membrane fraction of MSCs. Genetic engineering is a promising route in clinical settings, where nano-encapsulated technology strategies are combined. In this review, the mechanism underlying MSC homing and the advantages of MSC mimicking nanoencapsulations are discussed. In addition, genetic engineering of MSCs and MSC mimicking nanoencapsulation is described as a promising strategy for the treatment of immune-related diseases.

Kyungeun Kim,1 Dongwoo Khang1– 4 1College of Medicine, Gachon University, Incheon 21999, South Korea; 2Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea; 3Gachon Advanced Institute for Health Science & Technology (GAIHST), Gachon University, Incheon 21999, South Korea; 4Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South KoreaCorrespondence: Dongwoo KhangDepartment of Physiology, School of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon Advanced Institute for Health Science & Technology (GAIHST), Gachon University, Incheon 21999, South KoreaTel/Fax +82 32 899 1525Email dkhang@gachon.ac.krAbstract: This review aims to summarize the methods that have been used till today, highlight methods that are currently being developed, and predict the future roadmap for anticancer therapy. In the beginning of this review, established approaches for anticancer therapy, such as conventional chemotherapy, hormonal therapy, monoclonal antibodies, and tyrosine kinase inhibitors are summarized. To counteract the side effects of conventional chemotherapy and to increase limited anticancer efficacy, nanodrug- and stem cell-based therapies have been introduced. However, current level of understanding and strategies of nanodrug and stem cell-based therapies have limitations that make them inadequate for clinical application. Subsequently, this manuscript reviews methods with fewer side effects compared to those of the methods mentioned above which are currently being investigated and are already being applied in the clinic. The newer strategies that are already being clinically applied include cancer immunotherapy, especially T cell-mediated therapy and immune checkpoint inhibitors, and strategies that are gaining attention include the manipulation of the tumor microenvironment or the activation of dendritic cells. Tumor-associated macrophage repolarization is another potential strategy for cancer immunotherapy, a method which activates macrophages to immunologically attack malignant cells. At the end of this review, we discuss combination therapies, which are the future of cancer treatment. Nanoparticle-based anticancer immunotherapies seem to be effective, in that they effectively use nanodrugs to elicit a greater immune response. The combination of these therapies with others, such as photothermal or tumor vaccine therapy, can result in a greater anticancer effect. Thus, the future of anticancer therapy aims to increase the effectiveness of therapy using various therapies in a synergistic combination rather than individually.Keywords: stem cell-based therapy, T cell-mediated therapy, macrophage repolarization, nanodrug-based immunotherapy

Song Kwon,1,* Sung Hyun Kim,2,* Dongwoo Khang,1,3,4 Jong Yeon Lee2 1Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea; 2Department of Ophthalmology, Gil Medical Center, Gachon University, College of Medicine, Incheon 21565, South Korea; 3Department of Gachon Advanced Institute for Health Science & Technology (GAIHST), Gachon University, Incheon 21999, South Korea; 4Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea*These authors contributed equally to this workCorrespondence: Jong Yeon LeeDepartment of Ophthalmology, College of Medicine, Gachon University, Incheon 21565, South KoreaEmail jongyeonlee@gilhospital.comDongwoo KhangDepartment of Physiology, School of Medicine, Gachon University, Incheon 21999, South KoreaTel/ Fax +82 32 899 1525Email dkhang@gachon.ac.krAbstract: Glaucoma is a group of diseases characterized by progressive degeneration of retinal ganglion cells, leading to irreversible blindness. Currently, intraocular pressure reduction is the only established treatment available for glaucoma. With this treatment, the progression of the disease can only be delayed and there is no recovery. In addition, the commercially available eye drops have the disadvantage of low compliance and short therapeutic time, while glaucoma surgery always has the risk of failure due to wound fibrosis. Nanotechnology can overcome the limitations of the current treatment through the encapsulation and conjugation of drugs used for lowering intraocular pressure and antifibrotic agents using biodegradable or biocompatible nanoparticles for the sustained release of the drugs to protect the damaged ocular cells. Furthermore, using nanotechnology, treatment can be administered in various forms, including eye drops, contact lens, and ocular inserts, according to the convenience of the patients. Despite the promising results of delaying the progression of glaucoma, the regeneration of damaged ocular cells, including trabecular meshwork and retinal ganglion cells, is another critical hurdle to overcome. Bone marrow-derived mesenchymal stem cells and Müller glia cells can secrete neurogenic factors that trigger the regeneration of associated cells, including trabecular meshwork and retinal ganglion cells. In conclusion, this review highlights the potential therapeutic applications of nanotechnology- and stem cell-based methods that can be employed for the protection and regeneration of ocular cells.Keywords: glaucoma, ocular regeneration, protection, stem cell, nanotechnology

Song Kwon,1,* Kwai Han Yoo,2,* Sun Jin Sym,2 Dongwoo Khang1,3,41Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea; 2Department of Internal Medicine, Division of Hematology, School of Medicine, Gachon University Gil Medical Center, Incheon, 21565, South Korea; 3Department of Gachon Advanced Institute for Health Science & Technology (Gaihst), Gachon University, Incheon 21999, South Korea; 4Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea*These authors contributed equally to this workAbstract: Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.Keywords: glioblastoma multiforme, tumor inhibition, mesenchymal stem cell, nanocarrier, nerve regeneration, anti-inflammation