Overcoming Nanoparticle-Mediated Complement Activation by Surface PEG Pairing.

Many PEGylated nanoparticles activate the complement system, which is an integral component of innate immunity. This is of concern as uncontrolled complement activation is potentially detrimental and contributes to disease pathogenesis. Here, it is demonstrated that, in contrast to carboxyPEG2000-stabilized poly(lactic-co-glycolic acid) nanoparticles, surface camouflaging with appropriate combinations and proportions of carboxyPEG2000 and methoxyPEG550 can largely suppress nanoparticle-mediated complement activation through the lectin pathway. This is attributed to the ability of the short, rigid methoxyPEG550 chains to laterally compress carboxyPEG2000 molecules to become more stretched and assume an extended, random coil configuration. As supported by coarse-grained molecular dynamics simulations, these conformational attributes minimize statistical protein binding/intercalation, thereby affecting sequential dynamic processes in complement convertase assembly. Furthermore, PEG pairing has no additional effect on nanoparticle longevity in the blood and macrophage uptake. PEG pairing significantly overcomes nanoparticle-mediated complement activation without the need for surface functionalization with complement inhibitors.

Improvement of stem cell-derived exosome release efficiency by surface-modified nanoparticles.

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stromal cells that release extracellular vesicles (EVs). EVs contain various growth factors and antioxidants that can positively affect the surrounding cells. Nanoscale MSC-derived EVs, such as exosomes, have been developed as bio-stable nano-type materials. However, some issues, such as low yield and difficulty in quantification, limit their use. We hypothesized that enhancing exosome production using nanoparticles would stimulate the release of intracellular molecules. RESULTS: The aim of this study was to elucidate the molecular mechanisms of exosome generation by comparing the internalization of surface-modified, positively charged nanoparticles and exosome generation from MSCs. We determined that Rab7, a late endosome and auto-phagosome marker, was increased upon exosome expression and was associated with autophagosome formation. CONCLUSIONS: It was concluded that the nanoparticles we developed were transported to the lysosome by clathrin-mediated endocytosis. additionally, entered nanoparticles stimulated that autophagy related factors to release exosome from the MSC. MSC-derived exosomes using nanoparticles may increase exosome yield and enable the discovery of nanoparticle-induced genetic factors.

Biomimetic surface modification of discoidal polymeric particles.

The rationale for the design of drug delivery nanoparticles is traditionally based on co-solvent self-assembly following bottom-up approaches or in combination with top-down approaches leading to tailored physiochemical properties to regulate biological responses. However, the optimal design and control of material properties to achieve specific biological responses remain the central challenge in drug delivery research. Considering this goal, we herein designed discoidal polymeric particles (DPPs) whose surfaces are re-engineered with isolated red blood cell (RBC) membranes to tailor their pharmacokinetics. The RBC membrane-coated DPPs (RBC-DPPs) were found to be biocompatible in cell-based in vitro experiments and exhibited extended blood circulation half-life. They also demonstrated unique kinetics at later time points in a mouse model compared to that of bare DPPs. Our results suggested that the incorporation of biomimicry would enable the biomimetic particles to cooperate with systems in the body such as cells and biomolecules to achieve specific biomedical goals.

Non-Linear Cellular Dielectrophoretic Behavior Characterization Using Dielectrophoretic Tweezers-Based Force Spectroscopy inside a Microfluidic Device.

Characterization of cellular dielectrophoretic (DEP) behaviors, when cells are exposed to an alternating current (AC) electric field of varying frequency, is fundamentally important to many applications using dielectrophoresis. However, to date, that characterization has been performed with monotonically increasing or decreasing frequency, not with successive increases and decreases, even though cells might behave differently with those frequency modulations due to the nonlinear cellular electrodynamic responses reported in previous works. In this report, we present a method to trace the behaviors of numerous cells simultaneously at the single-cell level in a simple, robust manner using dielectrophoretic tweezers-based force spectroscopy. Using this method, the behaviors of more than 150 cells were traced in a single environment at the same time, while a modulated DEP force acted upon them, resulting in characterization of nonlinear DEP cellular behaviors and generation of different cross-over frequencies in living cells by modulating the DEP force. This study demonstrated that living cells can have non-linear di-polarized responses depending on the modulation direction of the applied frequency as well as providing a simple and reliable platform from which to measure a cellular cross-over frequency and characterize its nonlinear property.

Enhanced Homing Technique of Mesenchymal Stem Cells Using Iron Oxide Nanoparticles by Magnetic Attraction in Olfactory-Injured Mouse Models.

Intranasal delivery of mesenchymal stem cells (MSCs) to the olfactory bulb is a promising approach for treating olfactory injury. Additionally, using the homing phenomenon of MSCs may be clinically applicable for developing therapeutic cell carriers. Herein, using superparamagnetic iron oxide nanoparticles (SPIONs) and a permanent magnet, we demonstrated an enhanced homing effect in an olfactory model. Superparamagnetic iron oxide nanoparticles with rhodamine B (IRBs) had a diameter of 5.22 ± 0.9 nm and ζ-potential of +15.2 ± 0.3 mV. IRB concentration of 15 µg/mL was injected with SPIONs into MSCs, as cell viability significantly decreased when 20 μg/mL was used (p ≤ 0.005) compared to in controls. The cells exhibited magnetic attraction in vitro. SPIONs also stimulated CXCR4 (C-X-C chemokine receptor type 4) expression and CXCR4-SDF-1 (Stromal cell-derived factor 1) signaling in MSCs. After injecting magnetized MSCs, these cells were detected in the damaged olfactory bulb one week after injury on one side, and there was a significant increase compared to when non-magnetized MSCs were injected. Our results suggest that SPIONs-labeled MSCs migrated to injured olfactory tissue through guidance with a permanent magnet, resulting in better homing effects of MSCs in vivo, and that iron oxide nanoparticles can be used for internalization, various biological applications, and regenerative studies.

Multicomponent, Tumor-Homing Chitosan Nanoparticles for Cancer Imaging and Therapy.

Current clinical methods for cancer diagnosis and therapy have limitations, although survival periods are increasing as medical technologies develop. In most cancer cases, patient survival is closely related to cancer stage. Late-stage cancer after metastasis is very challenging to cure because current surgical removal of cancer is not precise enough and significantly affects bystander normal tissues. Moreover, the subsequent chemotherapy and radiation therapy affect not only malignant tumors, but also healthy tissues. Nanotechnologies for cancer treatment have the clear objective of solving these issues. Nanoparticles have been developed to more accurately differentiate early-stage malignant tumors and to treat only the tumors while dramatically minimizing side effects. In this review, we focus on recent chitosan-based nanoparticles developed with the goal of accurate cancer imaging and effective treatment. Regarding imaging applications, we review optical and magnetic resonance cancer imaging in particular. Regarding cancer treatments, we review various therapeutic methods that use chitosan-based nanoparticles, including chemo-, gene, photothermal, photodynamic and magnetic therapies.

Characterization of the Stiffness of Multiple Particles Trapped by Dielectrophoretic Tweezers in a Microfluidic Device.

Characterization of the stiffness of multiple particles trapped by tweezers-based force spectroscopy is a key step in building simple, high-throughput, and robust systems that can investigate the molecular interactions in a biological process, but the technology to characterize it in a given environment simultaneously is still lacking. We first characterized the stiffness of multiple particles trapped by dielectrophoretic (DEP) tweezers inside a microfluidic device. In this characterization, we developed a method to measure the thermal fluctuations of the trapped multiple particles with DEP tweezers by varying the heights of the particles in the given environment at the same time. Using the data measured in this controlled environment, we extracted the stiffness of the trapped particles and calculated their force. This study not only provides a simple and high-throughput method to measure the trap stiffness of multiple particles inside a microfluidic device using DEP tweezers but also inspires the application of the trapped multiple particles to investigate the dynamics in molecular interactions.

Hierarchically-Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation.

Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging; guidance under remote fields; heat generation; and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ~10 times (r2 ~ 835 (mM·s)-1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r2 relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ~ 65 fg) and the consequent generation of significant inter-particle magnetic dipole interactions. In tumor bearing mice, the silicon-based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (~ 0.5 mg of Fe/kg animal) as compared to current practice.

Positron emitting magnetic nanoconstructs for PET/MR imaging.

Hybrid PET/MRI scanners have the potential to provide fundamental molecular, cellular, and anatomic information essential for optimizing therapeutic and surgical interventions. However, their full utilization is currently limited by the lack of truly multi-modal contrast agents capable of exploiting the strengths of each modality. Here, we report on the development of long-circulating positron-emitting magnetic nanoconstructs (PEM) designed to image solid tumors for combined PET/MRI. PEMs are synthesized by a modified nano-precipitation method mixing poly(lactic-co-glycolic acid) (PLGA), lipids, and polyethylene glycol (PEG) chains with 5 nm iron oxide nanoparticles (USPIOs). PEM lipids are coupled with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and subsequently chelated to (64)Cu. PEMs show a diameter of 140 ± 7 nm and a transversal relaxivity r2 of 265.0 ± 10.0 (mM × s)(-1), with a r2/r1 ratio of 123. Using a murine xenograft model bearing human breast cancer cell line (MDA-MB-231), intravenously administered PEMs progressively accumulate in tumors reaching a maximum of 3.5 ± 0.25% ID/g tumor at 20 h post-injection. Correlation of PET and MRI signals revealed non-uniform intratumoral distribution of PEMs with focal areas of accumulation at the tumor periphery. These long-circulating PEMs with high transversal relaxivity and tumor accumulation may allow for detailed interrogation over multiple scales in a clinically relevant setting.

Diffusion of curcumin in PLGA-based carriers for drug delivery: a molecular dynamics study.

CONTEXT: The rapid growth and diversification of drug delivery systems have been significantly supported by advancements in micro- and nano-technologies, alongside the adoption of biodegradable polymeric materials like poly(lactic-co-glycolic acid) (PLGA) as microcarriers. These developments aim to reduce toxicity and enhance target specificity in drug delivery. The use of in silico methods, particularly molecular dynamics (MD) simulations, has emerged as a pivotal tool for predicting the dynamics of species within these systems. This approach aids in investigating drug delivery mechanisms, thereby reducing the costs associated with design and prototyping. In this study, we focus on elucidating the diffusion mechanisms in curcumin-loaded PLGA particles, which are critical for optimizing drug release and efficacy in therapeutic applications. METHODS: We utilized MD to explore the diffusion behavior of curcumin in PLGA drug delivery systems. The simulations, executed with GROMACS, modeled curcumin molecules in a representative volume element of PLGA chains and water, referencing molecular structures from the Protein Data Bank and employing the CHARMM force field. We generated PLGA chains of varying lengths using the Polymer Modeler tool and arranged them in a bulk-like environment with Packmol. The simulation protocol included steps for energy minimization, T and p equilibration, and calculation of the isotropic diffusion coefficient from the mean square displacement. The Taguchi method was applied to assess the effects of hydration level, PLGA chain length, and density on diffusion. RESULTS: Our results provide insight into the influence of PLGA chain length, hydration level, and polymer density on the diffusion coefficient of curcumin, offering a mechanistic understanding for the design of efficient drug delivery systems. The sensitivity analysis obtained through the Taguchi method identified hydration level and PLGA density as the most significant input parameters affecting curcumin diffusion, while the effect of PLGA chain length was negligible within the simulated range. We provided a regression equation capable to accurately fit MD results. The regression equation suggests that increases in hydration level and PLGA density result in a decrease in the diffusion coefficient.

Histologic evaluation of a catheter coated with paclitaxel PLGA nanoparticles in the internal jugular veins of rats.

The aim of this study is to investigate the potential impact of catheterization on intimal hyperplasia and explore the efficacy of Paclitaxel loaded PLGA nanoparticles (PTX-NPs) in preventing stenosis at the site of venous injury. Under general anesthesia, Central Venous Catheters were inserted into the rat's right internal jugular veins (IJV) using the cut-down technique. Twenty bare catheters (C) and twenty PTX-NPs coated catheters (P) were assigned to one of four groups (C2, C4, P2, or P4) based on catheter type and expected survival time. 2 or 4 weeks after surgery, IJVs were completely harvested by formalin fixation and gelatin infusion and slides were stained with H&E (Haematoxylin and Eosin) and Masson's technique. The P2 (Paclitaxel coating, 2 weeks) group showed the most proliferation among the four groups and the P4 (Paclitaxel coating, 4 weeks) showed a tendency to decrease proliferation. Additionally, the lumen size in the P4 group was about 6% smaller than in the P2 group, and there was a lower prevalence of stenotic grade in the P4 group. Our study suggests that PTX-NPs coated catheters may be effective in preventing venous stenosis if the intended usage is prolonged, rather than for a short-term period. Graphical abstract: Schematic representation of catheter functionalization and coating of PTX-NPs on Catheter. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00282-y.

Clinical Trials for Oral, Inhaled and Intravenous Drug Delivery System for Lung Cancer and Emerging Nanomedicine-Based Approaches.

Lung cancer is one of the most common malignant tumors worldwide and is characterized by high morbidity and mortality rates and a poor prognosis. It is the leading cause of cancer-related death in the United States and worldwide. Most patients with lung cancer are treated with chemotherapy, radiotherapy, or surgery; however, effective treatment options remain limited. In this review, we aim to provide an overview of clinical trials, ranging from Phase I to III, conducted on drug delivery systems for lung cancer treatment. The trials included oral, inhaled, and intravenous administration of therapeutics. Furthermore, the study also talks about the evolving paradigm of targeted therapy and immunotherapy providing promising directions for personalized treatment. In addition, we summarize the best results and limitations of these drug delivery systems and discuss the potential capacity of nanomedicine.

Cavitation-assisted sonothrombolysis by asymmetrical nanostars for accelerated thrombolysis.

Sonothrombolysis with recombinant tissue plasminogen activator (rtPA) and microbubbles has been widely studied to enhance thrombolytic potential. Here, we report different sonothrombolysis strategy in nanoparticles using microbubbles cavitation. We found that different particles in shape exhibited different reactivity toward the cavitation, leading to a distinct sonothrombolytic potential. Two different gold nanoparticles in shape were functionalized with the rtPA: rtPA-functionalized gold nanospheres (NPt) and gold nanostars (NSt). NPt could not accelerate the thrombolytic potential with a sole acoustic stimulus. Importantly, NSt enhanced the potential with acoustic stimulus and microbubble-mediated cavitation, while NPt were not reactive to cavitation. Coadministration of NSt and microbubbles resulted in a dramatic reduction of the infarcts in a photothrombotic model and recovery in the cerebral blood flow. Given the synergistic effect and in vivo feasibility of this strategy, cavitation-assisted sonothrombolysis by asymmetrical NSt might be useful for treating acute ischemic stroke.

Targeted thrombolysis by magnetoacoustic particles in photothrombotic stroke model.

BACKGROUND: Recombinant tissue plasminogen activator (rtPA) has a short half-life, and additional hemorrhagic transformation (HT) can occur when treatment is delayed. Here, we report the design and thrombolytic performance of 3 [Formula: see text]m discoidal polymeric particles loaded with rtPA and superparamagnetic iron oxide nanoparticles (SPIONs), referred to as rmDPPs, to address the HT issues of rtPA. METHODS: The rmDPPs consisted of a biodegradable polymeric matrix, rtPA, and SPIONs and were synthesized via a top-down fabrication. RESULTS: The rmDPPs could be concentrated at the target site with magnetic attraction, and then the rtPA could be released under acoustic stimulus. Therefore, we named that the particles had magnetoacoustic properties. For the in vitro blood clot lysis, the rmDPPs with magnetoacoustic stimuli could not enhance the lytic potential compared to the rmDPPs without stimulation. Furthermore, although the reduction of the infarcts in vivo was observed along with the magnetoacoustic stimuli in the rmDPPs, more enhancement was not achieved in comparison with the rtPA. A notable advantage of rmDPPs was shown in delayed administration of rmDPPs at poststroke. The late treatment of rmDPPs with magnetoacoustic stimuli could reduce the infarcts and lead to no additional HT issues, while rtPA alone could not show any favorable prognosis. CONCLUSION: The rmDPPs may be advantageous in delayed treatment of thrombotic patients.

Improved survival rate and minimal side effects of doxorubicin for lung metastasis using engineered discoidal polymeric particles.

Despite advances in cancer therapy, the discovery of effective cancer treatments remains challenging. In this study, a simple method was developed to increase the efficiency of doxorubicin (DOX) delivery in a lung metastasis model. This method comprises a simple configuration to increase the delivery efficiency via precise engineering of the size, shape, loading content, and biodegradability of the drug delivery system. This system had a 3 µm discoidal shape and exerted approximately 90% burst release of the drug within the first 24 h. There was no cytotoxicity of the drug carrier up to a concentration of 1 mg ml-1, and DOX from the carrier was delivered into the cancer cells, exhibiting an anticancer effect comparable to that of the free drug. The ex vivo results revealed a strong correlation between the location of cancer cells in the lung and the location of DOX delivered by this drug delivery system. These drug carriers were confirmed to intensively deliver DOX to cancer cells in the lung, with minimal off-target effects. These findings indicate that this delivery system can be a new approach to improving the survival rate and reducing the side effects caused by anticancer drugs without the use of targeting ligands and polyethylene glycol.

Protection of Hearing Loss in Ototoxic Mouse Model Through SPIONs and Dexamethasone-Loaded PLGA Nanoparticle Delivery by Magnetic Attraction.

Background: Ototoxicity currently has no available treatment other than medication withdrawal as soon as toxicity is suspected. The human inner ear organs have little potential for regeneration; thus, ototoxicity-induced hair cell injury is deemed permanent. Dexamethasone (Dexa) is a synthetic steroid analog that has significant potential for otoprotection in the treatment of various inner ear diseases; however, its low absorption into the inner ear prevents significant recovery of function. Nanoparticles facilitate targeted drug delivery, stabilize drug release, and increase half-life of the drug. Methods: This study aimed to develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded superparamagnetic iron oxide nanoparticles (SPIONs) and Dexa (PSD-NPs) to control localized drug delivery by magnetic attraction in the treatment of ototoxicity-induced hearing loss. PSD-NPs and without SPIONs (PD-NPs) were prepared using a nanoprecipitation method. Results: Using an inner ear simulating system, we confirmed that PSD-NPs has an otoprotective effect in organotypic culture that is enhanced by magnetic attraction. PSD-NPs delivered via intrabullar injection in a magnetic field penetrated the inner ear and prevented hearing loss progression to a greater degree than equivalent doses of Dexa or PSD-NPs alone (day 28: ototoxic: 80.0 ± 0.0 dB; Dexa 100: 60.0 ± 15.5 dB; PSD 100: 50.0 ± 8.2 dB; PSD 100 with magnet: 22.5 ± 5.0 dB; P < 0.05). The protective effects were confirmed in various in vivo and in vitro models of ototoxicity. Conclusion: Our findings suggest that SPIONs with Dexa and magnetic field application prevent the progression of ototoxicity-induced hearing loss through anti-apoptotic mechanisms in the inner ear.

Porous discoidal polymeric particles for effective drug delivery minimizing phagocytosis.

Curcumin has great potential in cancer treatment and prevention. However, free curcumin for anticancer effect is limited due to its low water solubility and instability. Delivery of free curcumin using biodegradable and biocompatible polymers, such as poly (lactic-co-glycolic acid) (PLGA), can improve these undesirable problems. In this study, a top-down fabrication method using PLGA was employed to deliver free curcumin, engineering size, shape, and surface properties. As a result, porous discoidal polymeric particles (DPPs) were produced in ammonium bicarbonate with a hydrodynamic diameter of 5 µm and a negatively charged surface. The loading amount of free curcumin in the porous DPPs was higher than non-porous DPPs. In vitro drug release study showed that curcumin release from porous DPPs was 1.4-fold higher than non-porous ones. The confocal microscopy and flow cytometry results demonstrated that porous DPPs decrease phagocytosis by macrophages than non-porous ones. This study suggests that porous DPPs have significant advantages for effective drug delivery of curcumin, minimizing phagocytosis.

Indocyanine Green-Loaded PLGA Nanoparticles Conjugated with Hyaluronic Acid Improve Target Specificity in Cervical Cancer Tumors.

PURPOSE: Indocyanine green (ICG) is a promising agent for intraoperative visualization of tumor tissues and sentinel lymph nodes in early-stage gynecological cancer. However, it has some limitations, including a short half-life and poor solubility in aqueous solutions. This study aimed to enhance the efficacy of near-infrared (NIR) fluorescence imaging by overcoming the shortcomings of ICG using a nano-drug delivery system and improve target specificity in cervical cancer. MATERIALS AND METHODS: ICG and poly(lactic-co-glycolic acid) (PLGA) conjugated with polyethylenimine (PEI) were assembled to enhance stability. Hyaluronic acid (HA) was coated on PEI-PLGA-ICG nanoparticles to target CD44-positive cancer cells. The manufactured HA-ICG-PLGA nanoparticles (HINPs) were evaluated in vitro and in vivo on cervical cancer cells (SiHa; CD44+) and human dermal cells (ccd986sk; CD44-), respectively, using NIR imaging to compare intracellular uptake and to quantify the fluorescence intensities of cells and tumors. RESULTS: HINPs were confirmed to have a mean size of 200 nm and a zeta-potential of 33 mV using dynamic light scattering. The stability of the HINPs was confirmed at pH 5.0-8.0. Cytotoxicity assays, intracellular uptake assays, and cervical cancer xenograft models revealed that, compared to free ICG, the HINPs had significantly higher internalization by cervical cancer cells than normal cells (p<0.001) and significantly higher accumulation in tumors (p<0.001) via CD44 receptor-mediated endocytosis. CONCLUSION: This study demonstrated the successful application of HINPs as nanocarriers for delivering ICG to CD44-positive cervical cancer, with improved efficacy in NIR fluorescence imaging.

Biodistribution of poly clustered superparamagnetic iron oxide nanoparticle labeled mesenchymal stem cells in aminoglycoside induced ototoxic mouse model.

Recently, application of stem cell therapy in regenerative medicine has become an active field of study. Mesenchymal stem cells (MSCs) are known to have a strong ability for homing. MSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) exhibit enhanced homing due to magnetic attraction. We have designed a SPION that has a cluster core of iron oxide-based nanoparticles coated with PLGA-Cy5.5. We optimized the nanoparticles for internalization to enable the transport of PCS nanoparticles through endocytosis into MSCs. The migration of magnetized MSCs with SPION by static magnets was seen in vitro. The auditory hair cells do not regenerate once damaged, ototoxic mouse model was generated by administration of kanamycin and furosemide. SPION labeled MSC's were administered through different injection routes in the ototoxic animal model. As result, the intratympanic administration group with magnet had the highest number of cells in the brain followed by the liver, cochlea, and kidney as compared to those in the control groups. The synthesized PCS (poly clustered superparamagnetic iron oxide) nanoparticles, together with MSCs, by magnetic attraction, could synergistically enhance stem cell delivery. The poly clustered superparamagnetic iron oxide nanoparticle labeled in the mesenchymal stem cells have increased the efficacy of homing of the MSC's to the target area by synergetic effect of magnetic attraction and chemotaxis (SDF-1/CXCR4 axis). This technique allows delivery of the stem cells to the areas with limited vasculatures. The nanoparticle in the biomedicine allows drug delivery, thus, the combination of nanomedicince together with the regenerative medicine will provide highly effective therapy.

Engineered iron oxide nanoparticles to improve regenerative effects of mesenchymal stem cells.

ABSTRACT: Mesenchymal stem cells (MSCs) based therapies are a major field of regenerative medicine. However, the success of MSC therapy relies on the efficiency of its delivery and retention, differentiation, and secreting paracrine factors at the target sites. Recent studies show that superparamagnetic iron oxide nanoparticles (SPIONs) modulate the regenerative effects of MSCs. After interacting with the cell membrane of MSCs, SPIONs can enter the cells via the endocytic pathway. The physicochemical properties of nanoparticles, including size, surface charge (zeta-potential), and surface ligand, influence their interactions with MSC, such as cellular uptake, cytotoxicity, homing factors, and regenerative related factors (VEGF, TGF-ß1). Therefore, in-depth knowledge of the physicochemical properties of SPIONs might be a promising lead in regenerative and anti-inflammation research using SPIONs mediated MSCs. In this review, recent research on SPIONs with MSCs and the various designs of SPIONs are examined and summarized. GRAPHIC ABSTRACT: A graphical abstract describes important parameters in the design of superparamagnetic iron oxide nanoparticles, affecting mesenchymal stem cells. These physicochemical properties are closely related to the mesenchymal stem cells to achieve improved cellular responses such as homing factors and cell uptake.