- Open Access
Application of magnetic nanoparticles in cell therapy
Stem Cell Research & Therapy volume 13, Article number: 135 (2022)
Fe3O4 magnetic nanoparticles (MNPs) are biomedical materials that have been approved by the FDA. To date, MNPs have been developed rapidly in nanomedicine and are of great significance. Stem cells and secretory vesicles can be used for tissue regeneration and repair. In cell therapy, MNPs which interact with external magnetic field are introduced to achieve the purpose of cell directional enrichment, while MRI to monitor cell distribution and drug delivery. This paper reviews the size optimization, response in external magnetic field and biomedical application of MNPs in cell therapy and provides a comprehensive view.
Stem cells have the function of tissue regeneration and repair. In addition, EVs and exosomes from cells also have the function of repairing injury. In particular, they have the attributes of low immunogenicity and drug delivery potential, and they carry a variety of signaling biomolecules (proteins, mRNAs and miRNAs). At present, stem cells and their secretory vesicles have been widely used in disease treatment. Researchers intravenously inject repair cells or vesicles into organisms to treat diseases, hoping that they can accumulate at the injured site via the blood circulation . The key is the successful delivery of drugs to the lesion. Although stem cells have homing ability, they still have shortcomings. The actual enrichment effect is not ideal [2, 3]. Kyrtatos et al.  showed data in vitro by computer simulation that a few cells were retained in the target tissue area in the presence of blood flow. By intracoronary injection, the cell residence time was only a few minutes in the study of myocardial regeneration . At the same time, EVs were cleared in a short time (1.2–1.3 min) after intravenous injection into the blood, and most of them accumulated in the liver and spleen. Therefore, the poor targeting, the low retention rate and the poor therapeutic effect limit the clinical application in cell therapy .
SPIONs have obvious advantages of low toxicity to organisms, magnetic targeting, magnetic resonance imaging tracking, hyperthermia and drug delivery ability. More importantly, SPIONs are an iron-containing preparation approved by the FDA. Therefore, the development of SPIONs has attracted increasing attention, especially in medicine. It is important to target and transport the therapeutic cells and EVs under the joint action of MNPs and an external magnetic field. This method can not only improve precise positioning within organisms [4, 7,8,9], improve the retention rate and prolong the drug half-life but also reduce the drug dosage and enhance the efficacy, even in high-flow systems (such as the arterial vascular system). In the literature [4, 10], it was found that targeted stem cells were enriched approximately five times more than nontargeted cells in arteries. After labeling with MNPs, EVs were preserved in the blood for 7–8 h in a magnetic field. Magnetic targeting was found to enhance myocardial retention of intravascular EPCs. They could also effectively cross the BBB and deliver drugs [11, 12] under a magnetic field. Therefore, cells and EVs labeled by MNPs achieved multiple functions of treatment, targeting, drug delivery, magnetic hyperthermia and MRI, which has a great development potential in medicine.
Here, we introduce the combination of MNPs not only with cells, but also with extracellular vesicles, exosomes and artificial simulated liposomes (known as membrane system or membrane structure for convenience). In this paper, we review the requirements for the size of MNPs when used in combination with membrane systems, the response under external magnetic field and its application in medicine.
Application size of MNPs
In this paper, we have reviewed the literature from the last 20 years and further explained the importance of the appropriate size of MNPs in Table 1.
A total of 36 literature studies are counted in Table 1. There are 14 articles on loading MNPs into cells, 2 articles on loading MNPs into vesicles, 11 articles on exosomes and 6 articles on liposomes. Table 1 shows that most researchers prefer to use MNPs of approximately 10 nm in the field of nanomedicine, because there are 25 literature studies introducing MNPs of 5–15 nm, accounting for 69%. This is consistent with the results in the literature [47, 48]. MNPs (< 200 nm) are rapidly filtered by the spleen and liver and cleared by the kidney at 2 nm, while 10-nm particles easily enter the circulatory system. Moreover, in the process of preparing MNPs, ultra-small magnetic particles (< 5 nm) have very good dispersion and stability in the organic coating. However, the response to external magnetic field is poor. Therefore, it is less used for magnetic targeting in cell therapy and more used as MRI contrast agent. When the size increases to 10 nm, it not only enhances the dispersion, but also enhances the response to the external magnetic field. In addition, with the continuous expansion of the scale, its agglomeration phenomenon is becoming more and more serious. Combined with the results summarized in the literature , the hydrodynamic size advantages  and optimization  of MNPs, we believe that a core diameter of approximately 10 nm has great advantages. At the same time, when preparing MNPs-labeled exosomes, the size of exosomes should be considered to facilitate the loading of MNPs. In addition, there are two main types of MNPs, namely Fe3O4 and γ-Fe2O3, but γ-Fe2O3 is better and safer for cells because ferric iron causes less damage to the recipient cells.
Effect of the magnetic field on the cells labeled by MNPs
The process of labeling cells with MNPs includes simple culture, transfection agents, magnetoelectric perforation and magnetoacoustic perforation . The small volume and negative surface charge of MNPs are conducive to their nonspecific adsorption on the plasma membrane, thus triggering their endocytosis pathway in cells . MNPs were ingested by cells and encapsulated in endosomes inside the cells. The endosomes were located close to the cytoplasm and away from the nucleus and not affected the normal activity of the cell. Analysis of the intracellular MNP distribution in the literature  showed that the MNP vesicles captured by cells diffuse along the cytoplasm and respond to magnetic fields , as shown in Fig. 1. A review  indicated that endosomes were elongated and aligned in the direction of the magnetic force line after the cells had phagocytized anionic colloidal ferromagnetic nanoparticles into the endosomes. In addition, the cells movement depended on the gradient in the magnetic field instead of feeling the strength [53,54,55]. The cells migrated toward the region with the maximum gradient. The study on the survival rate and proliferation rate of BMSCs under a high-intensity static magnetic field suggested that it had the least effect on cell proliferation within 24 h . The effect depended on the degree of iron load . If applied for a short time, cells can withstand a higher magnetic force. Moreover, stem cells were induced to differentiate by an extremely low-frequency magnetic field to obtain an ideal phenotype [57,58,59]. A study  revealed that the rotational movement of SPIONs induced by a dynamic magnetic field led to changes in cell membrane permeability and even apoptosis, because applying magnetic force to SPIONs distorted the inner membrane of the cell . At the same time, the vesicles encapsulating MNPs not existed in cells for a long time and were soon excreted by cells to form free labeled extracellular vesicles.
In summary, the key is to pay attention to the load of MNPs, the strength and time in the magnetic field and the preparation time of cells' sample. Because of the long time, the vesicles encapsulating MNPs were produced in the test, as shown in Fig. 2.
Application of MNP-labeled membrane systems in biomedicine
Application of MNP-labeled cells in biomedicine
Stem cells and secreted vesicles have multidirectional differentiation potential, migrate to inflammatory sites and repair tissues and regenerate . Therefore, they are widely used in cell therapy and have great prospects in the field of regenerative medicine. Stem cells have homing ability. However, they still have limitations and deficiencies. When stem cells are injected intravenously into the body, they are easily dispersed by blood flow and cleared by organisms, resulting in difficult localization, a short half-life and a low retention rate. To enhance targeting ability, prolong the retention rate and enhance the therapeutic effect of stem cells, MNPs are introduced. In addition, it was also important to minimize the injection dose, the toxicity and the side effects on healthy tissues and to cause the labeled cells or EVs to accumulate in the target tissue to reduce the in vitro administration concentration and frequency. As shown in Table 1, stem cells were labeled with MNPs and then injected into organisms under the magnetic field to treat lung injury , atrial fibrillation , coronary artery embolism , vascular diseases , systemic osteoporosis , retinitis , high intraocular pressure , Parkinson’s disease [40, 65], myocardial infarction  and spinal cord injury  and to regenerate articular cartilage and bone [66,67,68,69,70,71].
As shown in Fig. 2, MNP is engulfed by stem cells to form endosomes, which are then transformed into MVEs. The MVEs have two fates. One is to combine with lysosomes (low pH) in cells, be further digested and decomposed into Fe3+. The free metal ions released into the cytoplasm promote pathways of JNK activation and c-Jun phosphorylation, cause the upregulation of a variety of cytokines in cells, and induce angiogenesis, anti-apoptosis and anti-inflammatory . Moreover, in the treatment of myocardial infarction, it was found to induce the increased expression of connexin 43 (Cx43) in H9c2 . However, the other is excreted outside the cell in the form of extracellular vesicles. At the same time, exosomes prepared with MSC-IONP also contained a large number of therapeutic growth factors .
Application of MNP-labeled EVs in biomedicine
In the past decade, there have been an increasing number of studies on EVs, especially exosomes (50–150 nm). Due to the biological characteristics such as low immunogenicity and drug delivery, they have better application prospects in the field of tissue regeneration . EVs are effectors of intercellular communication and act as natural endogenous carriers. To improve their low separation rate and insufficient targeting ability, MNPs and magnetic localization were used to enhance the directional distribution ability of EVs. To internalize SPIONs directly into EVs, electroporation, natural incubation and other methods were used. However, the membrane is incomplete due to electroporation. MNP-labeled cells' secretory vesicles are the primary choice for natural processes. Under the external magnetic field, MNP-labeled EVs were concentrated and enriched at the target position for tissue repair and regeneration. Many studies have used this method to improve and treat scar formation in acute and chronic porcine myocardial infarction , ischemic stroke , skin trauma , spinal cord injury [43, 73], infarcted heart , wound healing , bone and angiogenesis , and myocardial infarction .
Application of magnetic liposomes in biomedicine
Liposomes are similar to EVs released by cells. Synthetic liposomes are usually spherical closed structures composed of lipid bilayers enclosing the internal hydrophilic chamber . The size of liposomes ranges from 20 nm to several microns . Like vesicles released by cells, liposomes can encapsulate molecules with different solubilities. Liposomes have the advantage of encapsulating MNPs without being affected by enzyme degradation, but there are no proteins or other biomolecules from precursor cells . At the same time, loading hydrophilic USPIO into the hydrophilic chamber of liposome can also achieve the magnetic targeting , drug delivery and MRI imaging [21, 78, 79] and generate multifunctional liposomes [77, 80]. Moreover, the preparation of liposomes is simple and controllable, so researchers have given increasing attention to the use of liposomes. Under a permanent magnetic field, magnetic liposomes deform into slender ellipsoids . A study  first reported the fusion of dry magnetic liposomes and cell membrane models, evaluated their interactions (giant monolayer vesicles, GUVs) and considered the future application in drug delivery of such magnetic systems. Ideally, the target release system allows external control of the time and dose of products released at the target location .
In summary, the application of the MNP-labeled membrane systems has treated many diseases successfully. In addition, the method can also be extended to the cell localization of other organs and provide a useful tool for systematic cell therapy. At the same time, it can also treat acute organ failure with high mortality. For example, acute lung injury and acute kidney injury are caused by COVID-19 or other diseases. However, there are few studies on these diseases. Combined with the rapid targeting enrichment and the therapeutic advantages of stem cells and exosomes, it will be possible to treat acute organ failure.
Tumor treatment with magnetic hyperthermia
In addition to tissue repair and regeneration, the combination of MNPs and membrane systems is also used to treat tumors. By changing the frequency of the external magnetic field, the high-speed movement of MNPs can be controlled. The magnetic fields mentioned here include the high-frequency and the low-frequency magnetic field. The high-frequency AMF makes MNPs in organism rotate at high speed, increase membrane permeability [11, 16, 21], enhance drug release, and even tear cell membrane . It can also convert magnetic energy into heat to kill tumor cells. Protect the surrounding environment while the local temperature far exceeds the body temperature . The damaging effect of magnetic hyperthermia on microglial BV2 cells  and increasing drug release  were studied. However, under a low-frequency magnetic field, the mechanism of destroying the membrane was mechanical and not dependent on heat. Therefore, nonspecific heating of surrounding tissues caused by AMF is avoided .
According to the literature for magnetic hyperthermia, in this paper, we mainly reviewed the combination of MNPs and membrane systems for magnetic hyperthermia to treat tumors. Therefore, the use of only heated MNP to kill tumors is not described here. Cell communication promotes tumor development through vesicles. It is believed that the vesicles are used as Trojan horses to provide a therapeutic payload for cancer cells . Therefore, exosomes in blood were combined with MNPs to target cancer . Recently, it was reported that SPION-modified exosomes transferred TNF-α to cancer cells through magnetic targeting and significantly inhibited tumor growth .
With regard to the study of magnetic liposomes, the literature studies [81, 85, 86] have reported the possibility of using magnetic liposomes and in vitro magnets to treat solid tumors. Some reports [84, 87] prepared multifunctional magnetoliposomes loaded with the anticancer drug DOX to inhibit cancer. In high-frequency magnetic field, multifunctional liposomes cause perforation effect or change the permeability of vesicle membrane through local heating to increase drug release . This method opens up a new prospect for the development of intelligent drug delivery system.
MRI application of MNP-labeled membrane systems
MNP-labeled membrane systems were used for three-dimensional noninvasive imaging positioning to achieve real-time monitoring of biological distribution in vivo [47, 89,90,91,92], as well as MRI of embryonic tissue [93, 94], adipose [95, 96], human adipose-derived stem cells [97, 98] and extracellular vesicles [99,100,101]. The dual exogenous substances in which cells are incubated with photosensitizers and MNPs  provide magnetic and optical responsiveness to vesicles for treatment and monitoring distribution. In addition to the situation described above, MNPs were encapsulated in liposomes together with fluorescent nanoparticles , rhodamine labeling  and quantum dots  for tracking. In conclusion, the application of MNP-labeled membrane systems can simultaneously have the advantages of treatment and visualization, so as to timely monitor the embolism caused by foreign substances and evaluate the metabolism.
Conclusions and expectations
This paper reviews the research progress of the application of MNP-labeled membrane systems in biomedicine. They have a wide range of applications in medicine and open up a potential application prospect for the directional positioning of biological entities. Through the perfect combination and utilization of magnetic targeting, MRI and magnetic hyperthermia, many diseases are expected to be successfully treated. In particular, through the continuous progress of magnetic field design, noninvasive treatment of deep diseases can be realized, not just on the surface of the body. The development of MNPs in precision medicine needs more exploration. In the future, it is expected to achieve more mature, comprehensive (systematic) and accurate (positioning) disease treatment in medicine.
Availability of data and materials
The data used to support the findings of this study are available from the corresponding author upon request.
Superparamagnetic iron oxide nanoparticles
Ultra-small superparamagnetic iron oxide
Human primary adipose-derived stem cells
Human mesenchymal stem cells
Mesenchymal stromal cells
Neural stem cells
Embryonic stem cells
Endothelial progenitor cells
Magnetic resonance imaging
Tumor necrosis factor
Iron oxide nanoparticle
Mature multivesicular endosomes Alternating magnetic field(AMF)
Alternating magnetic field
Them K, Salamon J, Szwargulski P, Sequeira S, Kaul MG, Lange C, et al. Increasing the sensitivity for stem cell monitoring in system-function based magnetic particle imaging. Phys Med Biol. 2016;61:3279–90. https://doi.org/10.1088/0031-9155/61/9/3279.
Hristov M, Weber C. The therapeutic potential of progenitor cells in ischemic heart disease. Basic Res Cardiol. 2006;101:1–7. https://doi.org/10.1007/s00395-005-0573-0.
Charwat S, Gyöngyösi M, Lang I, Graf S, Beran G, Hemetsberger R, et al. Role of adult bone marrow stem cells in the repair of ischemic myocardium: current state of the art. Exp Hematol. 2008;36:672–80.
Kyrtatos PG, Lehtolainen P, Junemann-Ramirez M, Garcia-Prieto A, Price AN, Martin JF, et al. Magnetic tagging increases delivery of circulating progenitors in vascular injury. JACC Cardiovasc Interv. 2009;2:794–802. https://doi.org/10.1016/j.jcin.2009.05.014.
Roncalli JG, Tongers J, Renault M-A, Losordo DW. Endothelial progenitor cells in regenerative medicine and cancer: a decade of research. Trends Biotechnol. 2008;26:276–83. https://doi.org/10.1016/j.tibtech.2008.01.005.
Zhuo Z, Wang J, Luo Y, Zeng R, Zhang C, Zhou W, et al. Targeted extracellular vesicle delivery systems employing superparamagnetic iron oxide nanoparticles. Acta Biomater. 2021. https://doi.org/10.1016/j.actbio.2021.07.027.
Consigny PM, Silverberg DA, Vitali NJ. Use of endothelial cells containing superparamagnetic microspheres to improve endothelial cell delivery to arterial surfaces after angioplasty. J Vasc Interv Radiol JVIR. 1999;10:155.
Pislaru SV, Harbuzariu A, Gulati R, Witt T, Sandhu NP, Simari RD, et al. Magnetically targeted endothelial cell localization in stented vessels. J Am Coll Cardiol. 2006;48:1839–45.
Pislaru SV. Magnetic forces enable rapid endothelialization of synthetic vascular grafts. Circulation. 2006;114:314–8.
Zhang B, Mo X, Yu F, Ma Y, Yan F. Ultrasound monitoring of magnet-guided delivery of mesenchymal stem cells labeled with magnetic lipid-polymer hybrid nanobubbles. Biomater Sci. 2020;8:3628–39. https://doi.org/10.1039/d0bm00473a.
Guardia P, Di Corato R, Lartigue L, Wilhelm C, Espinosa A, Garcia-Hernandez M, et al. Water-soluble iron oxide nanocubes with high values of specific absorption rate for cancer cell hyperthermia treatment. ACS Nano. 2012;6:3080–91. https://doi.org/10.1021/nn2048137.
Amstad E, Kohlbrecher J, Müller E, Schweizer T, Textor M, Reimhult E. Triggered release from liposomes through magnetic actuation of iron oxide nanoparticle containing membranes. Nano Lett. 2011;11:1664–70. https://doi.org/10.1021/nl2001499.
Wilhelm C, Cebers A, Bacri JC, Gazeau F. Deformation of intracellular endosomes under a magnetic field. Eur Biophys J. 2003;32:655–60.
Béalle G, Di Corato R, Kolosnjaj-Tabi J, Dupuis V, Clément O, Gazeau F, et al. Ultra magnetic liposomes for MR imaging, targeting, and hyperthermia. Langmuir. 2012;28:11834–42. https://doi.org/10.1021/la3024716.
Mart RJ, Liem KP, Webb SJ. Creating functional vesicle assemblies from vesicles and nanoparticles. Pharm Res. 2009;26:1701–10. https://doi.org/10.1007/s11095-009-9880-8.
Dwivedi P, Kiran S, Han S, Dwivedi M, Khatik R, Fan R, et al. Magnetic targeting and ultrasound activation of liposome-microbubble conjugate for enhanced delivery of anticancer therapies. ACS Appl Mater Interfaces. 2020;12:23737–51. https://doi.org/10.1021/acsami.0c05308.
Calatayud MP, Soler E, Torres TE, Campos-Gonzalez E, Junquera C, Ibarra MR, et al. Cell damage produced by magnetic fluid hyperthermia on microglial BV2 cells. Sci Rep. 2017;7:8627. https://doi.org/10.1038/s41598-017-09059-7.
Mart RJ, Liem KP, Webb SJ. Magnetically-controlled release from hydrogel-supported vesicle assemblies. Chem Commun (Camb). 2009. https://doi.org/10.1039/b901472a.
Martina M-S, Wilhelm C, Lesieur S. The effect of magnetic targeting on the uptake of magnetic-fluid-loaded liposomes by human prostatic adenocarcinoma cells. Biomaterials. 2008;29:4137–45. https://doi.org/10.1016/j.biomaterials.2008.07.011.
Wilhelm C, Lavialle F, Péchoux C, Tatischeff I, Gazeau F. Intracellular trafficking of magnetic nanoparticles to design multifunctional biovesicles. Small. 2008;4:577–82. https://doi.org/10.1002/smll.200700523.
Bulte J, Cuyper M, Despres D, Frank JA. Preparation, relaxometry, and biokinetics of PEGylated magnetoliposomes as MR contrast agent. J Magn Magn Mater. 1999;194:204–9.
Liu S, Chen X, Bao L, Liu T, Yuan P, Yang X, et al. Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles. Nat Biomed Eng. 2020;4:1063–75. https://doi.org/10.1038/s41551-020-00637-1.
Wu D, Kang L, Tian J, Wu Y, Liu J, Li Z, et al. Exosomes derived from bone mesenchymal stem cells with the stimulation of FeO nanoparticles and static magnetic field enhance wound healing through upregulated miR-21-5p. Int J Nanomed. 2020;15:7979–93. https://doi.org/10.2147/IJN.S275650.
Jung KO, Jo H, Yu JH, Gambhir SS, Pratx G. Development and MPI tracking of novel hypoxia-targeted theranostic exosomes. Biomaterials. 2018;177:139–48. https://doi.org/10.1016/j.biomaterials.2018.05.048.
Qi H, Liu C, Long L, Ren Y, Zhang S, Chang X, et al. Blood exosomes endowed with magnetic and targeting properties for cancer therapy. ACS Nano. 2016;10:3323–33. https://doi.org/10.1021/acsnano.5b06939.
Qi H, Yang L, Li X, Zhan Q, Han D, Zhao J, et al. Exosomes separated based on the “STOP” criteria for tumor-targeted drug delivery. J Mater Chem B. 2018;6:2758–68. https://doi.org/10.1039/c8tb00355f.
Li X, Wang Y, Shi L, Li B, Li J, Wei Z, et al. Magnetic targeting enhances the cutaneous wound healing effects of human mesenchymal stem cell-derived iron oxide exosomes. J Nanobiotechnol. 2020;18:113. https://doi.org/10.1186/s12951-020-00670-x.
Zhuang M, Chen X, Du D, Shi J, Deng M, Long Q, et al. SPION decorated exosome delivery of TNF-α to cancer cell membranes through magnetism. Nanoscale. 2020;12:173–88. https://doi.org/10.1039/c9nr05865f.
Zhuang M, Du D, Pu L, Song H, Deng M, Long Q, et al. SPION-decorated exosome delivered BAY55-9837 targeting the pancreas through magnetism to improve the blood GLC response. Small. 2019;15: e1903135. https://doi.org/10.1002/smll.201903135.
Snider EJ, Kubelick KP, Tweed K, Kim RK, Li Y, Gao K, et al. Improving stem cell delivery to the trabecular meshwork using magnetic nanoparticles. Sci Rep. 2018;8:12251. https://doi.org/10.1038/s41598-018-30834-7.
Tukmachev D, Lunov O, Zablotskii V, Dejneka A, Babic M, Syková E, et al. An effective strategy of magnetic stem cell delivery for spinal cord injury therapy. Nanoscale. 2015;7:3954–8. https://doi.org/10.1039/c4nr05791k.
Vaněček V, Zablotskii V, Forostyak S, Růžička J, Herynek V, Babič M, et al. Highly efficient magnetic targeting of mesenchymal stem cells in spinal cord injury. Int J Nanomed. 2012;7:3719–30. https://doi.org/10.2147/IJN.S32824.
Yin PT, Shah S, Pasquale NJ, Garbuzenko OB, Minko T, Lee K-B. Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer. Biomaterials. 2016;81:46–57. https://doi.org/10.1016/j.biomaterials.2015.11.023.
Andreas K, Georgieva R, Ladwig M, Mueller S, Notter M, Sittinger M, et al. Highly efficient magnetic stem cell labeling with citrate-coated superparamagnetic iron oxide nanoparticles for MRI tracking. Biomaterials. 2012;33:4515–25. https://doi.org/10.1016/j.biomaterials.2012.02.064.
Du V, Luciani N, Richard S, Mary G, Gay C, Mazuel F, et al. A 3D magnetic tissue stretcher for remote mechanical control of embryonic stem cell differentiation. Nat Commun. 2017;8:400. https://doi.org/10.1038/s41467-017-00543-2.
Labusca L, Herea D-D, Danceanu C-M, Minuti AE, Stavila C, Grigoras M, et al. The effect of magnetic field exposure on differentiation of magnetite nanoparticle-loaded adipose-derived stem cells. Mater Sci Eng C Mater Biol Appl. 2020;109: 110652. https://doi.org/10.1016/j.msec.2020.110652.
Ishii M, Shibata R, Numaguchi Y, Kito T, Suzuki H, Shimizu K, et al. Enhanced angiogenesis by transplantation of mesenchymal stem cell sheet created by a novel magnetic tissue engineering method. Arterioscler Thromb Vasc Biol. 2011;31:2210–5. https://doi.org/10.1161/ATVBAHA.111.231100.
Lu C-W, Hung Y, Hsiao J-K, Yao M, Chung T-H, Lin Y-S, et al. Bifunctional magnetic silica nanoparticles for highly efficient human stem cell labeling. Nano Lett. 2007;7:149–54.
Silva LHA, Silva MC, Vieira JB, Lima ECD, Silva RC, Weiss DJ, et al. Magnetic targeting increases mesenchymal stromal cell retention in lungs and enhances beneficial effects on pulmonary damage in experimental silicosis. Stem Cells Transl Med. 2020;9:1244–56. https://doi.org/10.1002/sctm.20-0004.
Moayeri A, Darvishi M, Amraei M. Homing of super paramagnetic iron oxide nanoparticles (SPIONs) labeled adipose-derived stem cells by magnetic attraction in a rat model of Parkinson’s disease. Int J Nanomed. 2020;15:1297–308. https://doi.org/10.2147/IJN.S238266.
Yun S, Shin T-H, Lee J-H, Cho MH, Kim I-S, Kim J-W, et al. Design of magnetically labeled cells (Mag-Cells) for in vivo control of stem cell migration and differentiation. Nano Lett. 2018;18:838–45. https://doi.org/10.1021/acs.nanolett.7b04089.
Han J, Kim B, Shin J-Y, Ryu S, Noh M, Woo J, et al. Iron oxide nanoparticle-mediated development of cellular gap junction crosstalk to improve mesenchymal stem cells’ therapeutic efficacy for myocardial infarction. ACS Nano. 2015;9:2805–19. https://doi.org/10.1021/nn506732n.
Kim HY, Kumar H, Jo M-J, Kim J, Yoon J-K, Lee J-R, et al. Therapeutic efficacy-potentiated and diseased organ-targeting nanovesicles derived from mesenchymal stem cells for spinal cord injury treatment. Nano Lett. 2018;18:4965–75. https://doi.org/10.1021/acs.nanolett.8b01816.
Kim HY, Kim TJ, Kang L, Kim Y-J, Kang MK, Kim J, et al. Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. Biomaterials. 2020;243: 119942. https://doi.org/10.1016/j.biomaterials.2020.119942.
Lee J-R, Park B-W, Kim J, Choo YW, Kim HY, Yoon J-K, et al. Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair. Sci Adv. 2020;6:eaaz0952. https://doi.org/10.1126/sciadv.aaz0952.
Wang J, Chen P, Dong Y, Xie H, Wang Y, Soto F, et al. Designer exosomes enabling tumor targeted efficient chemo/gene/photothermal therapy. Biomaterials. 2021;276: 121056. https://doi.org/10.1016/j.biomaterials.2021.121056.
Daldrup-Link HE, Golovko D, Ruffell B, Denardo DG, Castaneda R, Ansari C, et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin Cancer Res. 2011;17:5695–704. https://doi.org/10.1158/1078-0432.CCR-10-3420.
Chen J, Huang N, Ma B, Maitz MF, Wang J, Li J, et al. Guidance of stem cells to a target destination in vivo by magnetic nanoparticles in a magnetic field. ACS Appl Mater Interfaces. 2013;5:5976–85. https://doi.org/10.1021/am400249n.
Trekker J, Leten C, Struys T, Lazenka VV, Argibay B, Micholt L, et al. Sensitive in vivo cell detection using size-optimized superparamagnetic nanoparticles. Biomaterials. 2014;35:1627–35. https://doi.org/10.1016/j.biomaterials.2013.11.006.
Cromer Berman SM, Walczak P, Bulte JWM. Tracking stem cells using magnetic nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3:343–55. https://doi.org/10.1002/wnan.140.
Zhang L, Wang X. Coarse-grained modeling of vesicle responses to active rotational nanoparticles. Nanoscale. 2015;7:13458–67. https://doi.org/10.1039/c5nr01652e.
Zablotskii V, Polyakova T, Lunov O, Dejneka A. How a high-gradient magnetic field could affect cell life. Sci Rep. 2016;6:37407.
Miyakoshi J. Effects of static magnetic fields at the cellular level. Prog Biophys Mol Biol. 2005;87:213–23.
Romeo S, Sannino A, Scarfì MR, Massa R, d’Angelo R, Zeni O. Lack of effects on key cellular parameters of MRC-5 human lung fibroblasts exposed to 370 mT static magnetic field. Sci Rep. 2016;6:19398. https://doi.org/10.1038/srep19398.
Hore PJ. Are biochemical reactions affected by weak magnetic fields? Proc Natl Acad Sci USA. 2012;109:1357–8. https://doi.org/10.1073/pnas.1120531109.
Javani Jouni F, Abdolmaleki P, Movahedin M. Investigation on the effect of static magnetic field up to 15 mT on the viability and proliferation rate of rat bone marrow stem cells. In Vitro Cell Dev Biol Anim. 2013;49:212–9. https://doi.org/10.1007/s11626-013-9580-x.
Zablotskii V, Polyakova T, Dejneka A. Cells in the non-uniform magnetic world: how cells respond to high-gradient magnetic fields. BioEssays. 2018;40: e1800017. https://doi.org/10.1002/bies.201800017.
Shah B, Yin PT, Ghoshal S, Lee K-B. Multimodal magnetic core-shell nanoparticles for effective stem-cell differentiation and imaging. Angew Chem Int Ed Engl. 2013;52:6190–5. https://doi.org/10.1002/anie.201302245.
Yan J, Dong L, Zhang B, Qi N. Effects of extremely low-frequency magnetic field on growth and differentiation of human mesenchymal stem cells. Electromagn Biol Med. 2010;29:165–76. https://doi.org/10.3109/01676830.2010.505490.
Lepik KV, Muslimov AR, Timin AS, Sergeev VS, Romanyuk DS, Moiseev IS, et al. Mesenchymal stem cell magnetization: magnetic multilayer microcapsule uptake, toxicity, impact on functional properties, and perspectives for magnetic delivery. Adv Healthc Mater. 2016;5:3182–90. https://doi.org/10.1002/adhm.201600843.
Szili-Torok T, Akca F. Remote magnetic navigation in atrial fibrillation. Expert Rev Med Devices. 2012;9:249–55. https://doi.org/10.1586/erd.12.11.
Huang Z, Shen Y, Pei N, Sun A, Xu J, Song Y, et al. The effect of nonuniform magnetic targeting of intracoronary-delivering mesenchymal stem cells on coronary embolisation. Biomaterials. 2013;34:9905–16. https://doi.org/10.1016/j.biomaterials.2013.08.092.
Combined targeting of lentiviral vectors and positioning of transduced cells by magnetic nanoparticles. In: Proceedings of the National Academy of Sciences of the United States of America; 2009.
Yanai A, Häfeli UO, Metcalfe AL, Soema P, Addo L, Gregory-Evans CY, et al. Focused magnetic stem cell targeting to the retina using superparamagnetic iron oxide nanoparticles. Cell Transplant. 2012;21:1137–48. https://doi.org/10.3727/096368911X627435.
Stroh A, Boltze J, Sieland K, Hild K, Gutzeit C, Jung T, et al. Impact of magnetic labeling on human and mouse stem cells and their long-term magnetic resonance tracking in a rat model of Parkinson disease. Mol Imaging. 2009;8:166–78.
Ochi M. Mesenchymal stromal cell transplantation in the regeneration of articular cartilage and bone using a magnetic cell delivery system. J Am Acad Orthop Surg. 2013;21:61–2. https://doi.org/10.5435/JAAOS-21-01-61.
Sugioka T, Ochi M, Yasunaga Y, Adachi N, Yanada S. Accumulation of magnetically labeled rat mesenchymal stem cells using an external magnetic force, and their potential for bone regeneration. J Biomed Mater Res A. 2008;85:597–604.
Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, et al. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair. Arthroscopy. 2008;24:69–76. https://doi.org/10.1016/j.arthro.2007.08.017.
Ota Y, Kamei N, Tamaura T, Adachi N, Ochi M. Magnetic resonance imaging evaluation of cartilage repair and iron particle kinetics after magnetic delivery of stem cells. Tissue Eng Part C Methods. 2018;24:679–87. https://doi.org/10.1089/ten.TEC.2018.0263.
Mahmoud EE, Kamei G, Harada Y, Shimizu R, Kamei N, Adachi N, et al. Cell magnetic targeting system for repair of severe chronic osteochondral defect in a rabbit model. Cell Transplant. 2016;25:1073–83. https://doi.org/10.3727/096368915X689613.
Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, et al. Augmentation of degenerated human cartilage in vitro using magnetically labeled mesenchymal stem cells and an external magnetic device. Arthroscopy. 2009;25:1435–41. https://doi.org/10.1016/j.arthro.2009.06.009.
Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R, et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J. 2017;38:201–11. https://doi.org/10.1093/eurheartj/ehw240.
Lee J-R, Kyung JW, Kumar H, Kwon SP, Song SY, Han I-B, et al. Targeted delivery of mesenchymal stem cell-derived nanovesicles for spinal cord injury treatment. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21114185.
Wu D, Chang X, Tian J, Kang L, Wu Y, Liu J, et al. Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis. J Nanobiotechnol. 2021;19:209. https://doi.org/10.1186/s12951-021-00958-6.
Wang D, Ma B, Zhao Y, Sun Y, Luan Y, Wang J. Preparation and properties of semi-self-assembled lipopeptide vesicles. Langmuir. 2019;35:13174–81. https://doi.org/10.1021/acs.langmuir.9b02513.
Silva AKA, Kolosnjaj-Tabi J, Bonneau S, Marangon I, Boggetto N, Aubertin K, et al. Magnetic and photoresponsive theranosomes: translating cell-released vesicles into smart nanovectors for cancer therapy. ACS Nano. 2013;7:4954–66. https://doi.org/10.1021/nn400269x.
García-Jimeno S, Escribano E, Queralt J, Estelrich J. External magnetic field-induced selective biodistribution of magnetoliposomes in mice. Nanoscale Res Lett. 2012;7:452. https://doi.org/10.1186/1556-276X-7-452.
Nappini S, Bombelli FB, Bonini M, Nordèn B, Baglioni P. Magnetoliposomes for controlled drug release in the presence of low-frequency magnetic field. Soft Matter. 2009;6:154–62.
Bulte JW, De Cuyper M. Magnetoliposomes as contrast agents. Methods Enzymol. 2003;373:175–98.
Fattahi H, Laurent S, Liu F, Arsalani N, Vander Elst L, Muller RN. Magnetoliposomes as multimodal contrast agents for molecular imaging and cancer nanotheragnostics. Nanomedicine (Lond). 2011;6:529–44. https://doi.org/10.2217/nnm.11.14.
Sanson C, Diou O, Thévenot J, Ibarboure E, Soum A, Brûlet A, et al. Doxorubicin loaded magnetic polymersomes: theranostic nanocarriers for MR imaging and magneto-chemotherapy. ACS Nano. 2011;5:1122–40. https://doi.org/10.1021/nn102762f.
Rodrigues ARO, Gomes IT, Almeida BG, Araújo JP, Castanheira EMS, Coutinho PJG. Magnetic liposomes based on nickel ferrite nanoparticles for biomedical applications. Phys Chem Chem Phys. 2015;17:18011–21. https://doi.org/10.1039/c5cp01894c.
Reimhult E. Nanoparticle-triggered release from lipid membrane vesicles. New Biotechnol. 2015;32:665–72. https://doi.org/10.1016/j.nbt.2014.12.002.
Oliveira H, Pérez-Andrés E, Thevenot J, Sandre O, Berra E, Lecommandoux S. Magnetic field triggered drug release from polymersomes for cancer therapeutics. J Control Release. 2013;169:165–70. https://doi.org/10.1016/j.jconrel.2013.01.013.
Pradhan P, Giri J, Rieken F, Koch C, Mykhaylyk O, Döblinger M, et al. Targeted temperature sensitive magnetic liposomes for thermo-chemotherapy. J Control Release. 2010;142:108–21. https://doi.org/10.1016/j.jconrel.2009.10.002.
Fortin-Ripoche JP, Martina MS, Gazeau F, Menager C, Wilhelm C, Bacri JC, et al. Magnetic targeting of magnetoliposomes to solid tumors with MR imaging monitoring in mice: feasibility. Radiology. 2006;239:415–24.
Skouras A, Papadia K, Mourtas S, Klepetsanis P, Antimisiaris SG. Multifunctional doxorubicin-loaded magnetoliposomes with active and magnetic targeting properties. Eur J Pharm Sci. 2018;123:162–72. https://doi.org/10.1016/j.ejps.2018.07.044.
Feng A, Yuan J. Smart nanocontainers: progress on novel stimuli-responsive polymer vesicles. Macromol Rapid Commun. 2014;35:767–79. https://doi.org/10.1002/marc.201300866.
Long CM, Bulte JWM. In vivo tracking of cellular therapeutics using magnetic resonance imaging. Expert Opin Biol Ther. 2009;9:293–306. https://doi.org/10.1517/14712590802715723.
Hinds KA, Hill JM, Shapiro EM, Laukkanen MO, Silva AC, Combs CA, et al. Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood. 2003;102:867–72.
Hill JM. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation. 2003;108:1009–14.
Connell JJ, Patrick PS, Yu Y, Lythgoe MF, Kalber TL. Advanced cell therapies: targeting, tracking and actuation of cells with magnetic particles. Regen Med. 2015;10:757–72. https://doi.org/10.2217/rme.15.36.
Stroh A, Faber C, Neuberger T, Lorenz P, Sieland K, Jakob PM, et al. In vivo detection limits of magnetically labeled embryonic stem cells in the rat brain using high-field (17.6 T) magnetic resonance imaging. Neuroimage. 2005;24:635–45.
Crabbe A, Vandeputte C, Dresselaers T, Sacido AA, Verdugo JMG, Eyckmans J, et al. Effects of MRI contrast agents on the stem cell phenotype. Cell Transplant. 2010;19:919–36. https://doi.org/10.3727/096368910X494623.
Zhou S, Yin T, Zou Q, Zhang K, Gao G, Shapter JG, et al. Labeling adipose derived stem cell sheet by ultrasmall super-paramagnetic FeO nanoparticles and magnetic resonance tracking in vivo. Sci Rep. 2017;7:42793. https://doi.org/10.1038/srep42793.
Fan J, Tan Y, Jie L, Wu X, Yu R, Zhang M. Biological activity and magnetic resonance imaging of superparamagnetic iron oxide nanoparticles-labeled adipose-derived stem cells. Stem Cell Res Ther. 2013;4:44. https://doi.org/10.1186/scrt191.
Ha S, Ahn S, Kim S, Joo Y, Chong YH, Suh Y-H, et al. In vivo imaging of human adipose-derived stem cells in Alzheimer’s disease animal model. J Biomed Opt. 2014;19: 051206. https://doi.org/10.1117/1.JBO.19.5.051206.
Elfick A, Rischitor G, Mouras R, Azfer A, Lungaro L, Uhlarz M, et al. Biosynthesis of magnetic nanoparticles by human mesenchymal stem cells following transfection with the magnetotactic bacterial gene mms6. Sci Rep. 2017;7:39755. https://doi.org/10.1038/srep39755.
Dabrowska S, Del Fattore A, Karnas E, Frontczak-Baniewicz M, Kozlowska H, Muraca M, et al. Imaging of extracellular vesicles derived from human bone marrow mesenchymal stem cells using fluorescent and magnetic labels. Int J Nanomed. 2018;13:1653–64. https://doi.org/10.2147/IJN.S159404.
Chang M, Hsiao J-K, Yao M, Chien L-Y, Hsu S-C, Ko B-S, et al. Homologous RBC-derived vesicles as ultrasmall carriers of iron oxide for magnetic resonance imaging of stem cells. Nanotechnology. 2010;21: 235103. https://doi.org/10.1088/0957-4484/21/23/235103.
Liu T, Zhu Y, Zhao R, Wei X, Xin X. Visualization of exosomes from mesenchymal stem cells in vivo by magnetic resonance imaging. Magn Reson Imaging. 2020;68:75–82. https://doi.org/10.1016/j.mri.2020.02.001.
Beaune G, Ménager C, Cabuil V. Location of magnetic and fluorescent nanoparticles encapsulated inside giant liposomes. J Phys Chem B. 2008;112:7424–9. https://doi.org/10.1021/jp711811u.
Martina M-S, Fortin J-P, Fournier L, Ménager C, Gazeau F, Clément O, et al. Magnetic targeting of rhodamine-labeled superparamagnetic liposomes to solid tumors: in vivo tracking by fibered confocal fluorescence microscopy. Mol Imaging. 2007;6:140–6.
Beaune G, Dubertret B, Clément O, Vayssettes C, Cabuil V, Ménager C. Giant vesicles containing magnetic nanoparticles and quantum dots: feasibility and tracking by fiber confocal fluorescence microscopy. Angew Chem Int Ed Engl. 2007;46:5421–4.
Funding information is not applicable.
Ethics approval and consent to participate
Consent for publication
The authors declare no competing interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Chen, Y., Hou, S. Application of magnetic nanoparticles in cell therapy. Stem Cell Res Ther 13, 135 (2022). https://doi.org/10.1186/s13287-022-02808-0
- Cell therapy
- Magnetic targeting
- Drug delivery