Nanocarriers and macrophage interaction: from a potential hurdle to an alternative therapeutic strategy

• Naths Grazia Sukubo,
• Paolo Bigini and
• Annalisa Morelli

Beilstein J. Nanotechnol. 2025, 16, 97–118, doi:10.3762/bjnano.16.10

• from research to clinical application faces significant hurdles, primarily due to interactions with the mononuclear phagocyte system (MPS). After administration in host bodies, NCs encounter systems of phagocytic cells, predominantly resident macrophages such as Kupffer cells (KCs) in the liver and

Liver-targeting iron oxide nanoparticles and their complexes with plant extracts for biocompatibility

• Shushanik A. Kazaryan,
• Seda A. Oganian,
• Gayane S. Vardanyan,
• Anatolie S. Sidorenko and
• Ashkhen A. Hovhannisyan

Beilstein J. Nanotechnol. 2024, 15, 1593–1602, doi:10.3762/bjnano.15.125

• particles have been identified as 80–90% in the liver, 5–8% in the spleen, and 1–2% in the bone marrow [30]. One of the major organs where nanoparticles are likely to accumulate, depending on the route of administration, is the liver [31][32][33], where Kupffer cells can quickly uptake large nanoparticles

Recent updates in applications of nanomedicine for the treatment of hepatic fibrosis

• Damai Ria Setyawati,
• Fransiska Christydira Sekaringtyas,
• Riyona Desvy Pratiwi,
• A’liyatur Rosyidah,
• Rohimmahtunnissa Azhar,
• Nunik Gustini,
• Gita Syahputra,
• Idah Rosidah,
• Etik Mardliyati,
• Tarwadi and
• Sjaikhurrizal El Muttaqien

Beilstein J. Nanotechnol. 2024, 15, 1105–1116, doi:10.3762/bjnano.15.89

• in the liver [27][28]. The interaction of the nanocarriers with various types of cells is size-dependent [30]. Nanocarriers with a particle size bigger than 100 nm could be taken up by LSECs and Kupffer cells through endocytosis. With the increase of particle size, the uptake of nanocarriers by

• Kupffer cells is enhanced, leading to rapid accumulation of the nanocarriers in the liver with short blood circulation time [31]. In contrast, nanocarriers with a particle size smaller than 100 nm could avoid a capture by Kupffer cells. These nanocarriers then diffuse out of the sinusoids through the

• hepatobiliary clearance in vivo. For example, positively charged mesoporous silica NPs (MSNPs) underwent significant uptake by hepatocytes, while MSNPs with negative charges were rapidly internalized by Kupffer cells in liver sinusoids [33]. The negative charge of the nanocarriers could facilitate efficient

Entry of nanoparticles into cells and tissues: status and challenges

• Kirsten Sandvig,
• Tore Geir Iversen and
• Tore Skotland

Beilstein J. Nanotechnol. 2024, 15, 1017–1029, doi:10.3762/bjnano.15.83

• (Kupffer cells, i.e., the liver macrophages, liver sinusoidal endothelial cells (LSEC), and hepatocytes) in NP uptake [81]. A very recent study points to the importance of interactions between PEG-NPs with (apo)lipoproteins and scavenger receptors, and postulates that the high presence of these receptors

• on Kupffer cells and LSEC is responsible for the rapid uptake of PEG-NPs in the liver. The authors concluded that this is more important than macrophage interactions following NP opsonization [89]. One important outcome of ADME studies is to describe not only where in the body most of the particles

Recognition mechanisms of hemoglobin particles by monocytes – CD163 may just be one

• Jonathan-Gabriel Nimz,
• Pichayut Rerkshanandana,
• Chiraphat Kloypan,
• Ulrich Kalus,
• Saranya Chaiwaree,
• Axel Pruß,
• Radostina Georgieva,
• Yu Xiong and
• Hans Bäumler

Beilstein J. Nanotechnol. 2023, 14, 1028–1040, doi:10.3762/bjnano.14.85

• when using HbMPs as oxygen carriers [34]. In addition to transporting oxygen, HbMPs can also be used as drug carriers. However, in a pharmacokinetic study with HbMPs, accumulation of the particles in the sinusoids of the liver, where the Kupffer cells are located, was observed [35]. The mechanisms of

• and CD91 for Hpx, and taken up by phagocytes (e.g., Kupffer cells in liver sinoids), where Hb or heme are subsequently degraded. If this mechanism cannot be bypassed, Hp and Hpx must be fully saturated to achieve and maintain the effect of the HBOCs. Here is an example calculation with commercially

• after a short while in the MRI scan [24]. While the authors hypothesized that the HBOC was taken up by CD163-expressing Kupffer cells/macrophages, Chow et al. reported that when isolated rat livers were perfused with a HBOC solution, hepatocytes also took up abundant hemin, as determined by heme

Applications of superparamagnetic iron oxide nanoparticles in drug and therapeutic delivery, and biotechnological advancements

• Maria Suciu,
• Corina M. Ionescu,
• Alexandra Ciorita,
• Septimiu C. Tripon,
• Dragos Nica,
• Hani Al-Salami and
• Lucian Barbu-Tudoran

Beilstein J. Nanotechnol. 2020, 11, 1092–1109, doi:10.3762/bjnano.11.94

• were reported to be toxic in utero [92]. Highly negatively charged SPIONs were reported to be slightly toxic in vitro and in vivo. They are easily accumulated and degraded by the liver Kupffer cells and parenchymal cells [92][93][94]. The zeta potential and the ionic character of particles as well as

Luminescent gold nanoclusters for bioimaging applications

• Nonappa

Beilstein J. Nanotechnol. 2020, 11, 533–546, doi:10.3762/bjnano.11.42

• internalization of NCs in Kupffer cells. Histological studies of the organs revealed that there are no necrotic cells or atrophic tubes or specific immunogenic infiltration between 5 and 24 h post-injection. This indicates that there is no acute toxicity. X-ray tomography confirmed the uniform distribution of Au

Antitumor magnetic hyperthermia induced by RGD-functionalized Fe₃O₄ nanoparticles, in an experimental model of colorectal liver metastases

• Oihane K. Arriortua,
• Eneko Garaio,
• Borja Herrero de la Parte,
• Maite Insausti,
• Luis Lezama,
• Fernando Plazaola,
• Jose Angel García,
• Jesús M. Aizpurua,
• Maialen Sagartzazu,
• Mireia Irazola,
• Nestor Etxebarria,
• Ignacio García-Alonso,
• Alberto Saiz-López and
• José Javier Echevarria-Uraga

Beilstein J. Nanotechnol. 2016, 7, 1532–1542, doi:10.3762/bjnano.7.147

• Perls’ Prussian Blue stain concluded that deposits of iron could be observed within hepatic tissue, as blue dots corresponding to iron phagocytosis by Kupffer cells. On the other hand, when observing the tumor tissue, iron was seen as scattered deposits within the peripheral fibro-vascular matrix

• fluids containing Fe3O4@PMAO_RGD MNPs to the liver with colorectal tumor. A histological analysis showed that MNPs were distributed through the arterial vessels of the liver, without conforming aggregates or thrombosis. Nevertheless, the observation of MNPs as blue tags corresponding to Kupffer cells

• . EMR spectrum at room temperature for the Fe3O4@OA sample measured in toluene. SAR values versus applied magnetic field intensity (Happ) at different field frequencies for the Fe3O4@PMAO_RGD water dispersed nanoparticles. Kupffer cells with phagocytized iron deposits (blue dots) in liver tissue. In the

Overview about the localization of nanoparticles in tissue and cellular context by different imaging techniques

• Anja Ostrowski,
• Daniel Nordmeyer,
• Alexander Boreham,
• Cornelia Holzhausen,
• Lars Mundhenk,
• Christina Graf,
• Martina C. Meinke,
• Annika Vogt,
• Sabrina Hadam,
• Jürgen Lademann,
• Eckart Rühl,
• Ulrike Alexiev and
• Achim D. Gruber

Beilstein J. Nanotechnol. 2015, 6, 263–280, doi:10.3762/bjnano.6.25

• -inflammatory effects with rather specific accumulation in inflamed tissues [55][56][57]. Due to their sulfate groups and the specific staining properties of Alcian blue, this method has been used successfully, for example, for the detection of dPGS amine accumulated in Kupffer cells in the liver of mice

• to their negatively charged, sulfate rich shell. Organic dPGS amine accumulated in the cytoplasm of hepatic Kupffer cells (c, arrow). These liver specific macrophages are identified by their comma-shaped nuclei and their lining of hepatic sinusoids. Adjacent hepatocytes (c, asterisks) appear as light

• were clearly associated with the red pulp but not within lymphoid follicles (spared dots). (c) Light microscopic autoradiography with numerous radioactive decay-induced signals over Kupffer cells (arrows) in the liver of a mouse (left panel). Signals were sparse in adjacent hepatocytes with larger

The distribution and degradation of radiolabeled superparamagnetic iron oxide nanoparticles and quantum dots in mice

• Denise Bargheer,
• Artur Giemsa,
• Barbara Freund,
• Markus Heine,
• Christian Waurisch,
• Gordon M. Stachowski,
• Stephen G. Hickey,
• Alexander Eychmüller,
• Jörg Heeren and
• Peter Nielsen

Beilstein J. Nanotechnol. 2015, 6, 111–123, doi:10.3762/bjnano.6.11

• the Zn pool was observed. Confocal microscopy of rat liver cryosections (prepared 2 h after intravenous injection of polymer-coated Qdots) revealed a colocalization with markers for Kupffer cells and liver sinusoidal endothelial cells (LSEC), but not with hepatocytes. In J774 macrophages, fluorescent

• function by expressing several types of scavenger receptors and that Kupffer cells (KCs) belong to the family of macrophages and form part of the reticuloendothelial system. Thus, the sections were analyzed by immunofluorescence and stained for hepatic endothelial cells and Kupffer cells, which are known

• < 0.05), indicating an incomplete degradation of particles in the liver. Confocal microscopy of a cryosection of a rat liver 2h after intravenous injection of polymer-coated Qdots. The nuclei are stained with DAPI. Immunostaining of Kupffer cells (KCs, anti-CD31) and liver sinusoidal endothelial cells

The fate of a designed protein corona on nanoparticles in vitro and in vivo

• Denise Bargheer,
• Julius Nielsen,
• Gabriella Gébel,
• Markus Heine,
• Sunhild C. Salmen,
• Roland Stauber,
• Horst Weller,
• Joerg Heeren and
• Peter Nielsen

Beilstein J. Nanotechnol. 2015, 6, 36–46, doi:10.3762/bjnano.6.5

• adsorbed or covalently bound transferrin. This clearly indicates a fast processing of the nanoparticles within liver cells. Further experiments are needed to show which liver cells, besides Kupffer cells, are involved in the fast clearance of our NPs from blood and if the preformed transferrin corona plays

• phagocytes such as Kupffer cells in the liver. We found earlier by electron microscopy of murine liver tissues after i.v. injection of the polymer coated SPIO that these monodisperse iron cores are present in endosomal structures of Kupffer cells and liver sinusoidal endothelial cells [38]. These negative

Functionalized polystyrene nanoparticles as a platform for studying bio–nano interactions

• Cornelia Loos,
• Tatiana Syrovets,
• Anna Musyanovych,
• Volker Mailänder,
• Katharina Landfester,
• G. Ulrich Nienhaus and
• Thomas Simmet

Beilstein J. Nanotechnol. 2014, 5, 2403–2412, doi:10.3762/bjnano.5.250

• cytotoxicity of the SPIO nanoparticles [29][30]. These in vitro data are highly relevant for in vivo studies, because after intravenous injection, the carboxydextran-coated SPIO accumulate primarily in liver macrophages, so-called Kupffer cells, which constitute only about 2% of all liver cells, and remain

• there for prolonged periods of time [30]. The SPIO-loaded Kupffer cells undergo apoptotic cell death, which leads to partial depletion of Kupffer cells in the liver of mice five days after injection. The iron-mediated Kupffer cell toxicity in vivo could be prevented by the ROS scavenger edaravone

• numbers in tissues exposed to pathogens; for example, as alveolar macrophages in lungs, as Kupffer cells in the liver, and as sinusoidal lining cells in the spleen. Damaged or infected tissues contain a large number of macrophages, which originate from infiltrated monocytes. Thus, it is most likely that

In vitro and in vivo interactions of selected nanoparticles with rodent serum proteins and their consequences in biokinetics

• Wolfgang G. Kreyling,
• Stefanie Fertsch-Gapp,
• Martin Schäffler,
• Blair D. Johnston,
• Nadine Haberl,
• Christian Pfeiffer,
• Jörg Diendorf,
• Carsten Schleh,
• Stephanie Hirn,
• Manuela Semmler-Behnke,
• Matthias Epple and
• Wolfgang J. Parak

Beilstein J. Nanotechnol. 2014, 5, 1699–1711, doi:10.3762/bjnano.5.180

• mononuclear phagocyte system (MPS) with the largest fraction found in the liver. Indeed, more than 98% of AuNP with core diameters ≥ 18 nm were retained in the liver, particularly in Kupffer cells, and about 1–2% were retained in the spleen [11]. However, the smaller the AuNP were, the more they accumulated

The cell-type specific uptake of polymer-coated or micelle-embedded QDs and SPIOs does not provoke an acute pro-inflammatory response in the liver

• Markus Heine,
• Alexander Bartelt,
• Oliver T. Bruns,
• Denise Bargheer,
• Artur Giemsa,
• Barbara Freund,
• Ludger Scheja,
• Christian Waurisch,
• Alexander Eychmüller,
• Rudolph Reimer,
• Horst Weller,
• Peter Nielsen and
• Joerg Heeren

Beilstein J. Nanotechnol. 2014, 5, 1432–1440, doi:10.3762/bjnano.5.155

• type mice, we show that 30 min after injection polymer-coated nanocrystals are primarily taken up by liver sinusoidal endothelial cells. In contrast, by using wild type, Ldlr-/- as well as Apoe-/- mice we show that nanocrystals embedded within lipid micelles are internalized by Kupffer cells and, in a

• pro-inflammatory pathways. In conclusion, internalized nanocrystals at least in mouse liver cells, namely endothelial cells, Kupffer cells and hepatocytes are at least not acutely associated with potential adverse side effects, underlining their potential for biomedical applications. Keywords

• : hepatocytes; inflammation; Kupffer cells; liver sinusoidal endothelial cells; nanoparticle toxicity; nanoparticle uptake; quantum dots; superparamagnetic iron-oxide nanocrystals; Introduction The superior optical properties of QDs compared to organic dyes render them promising candidates for the demands of