Currently, nanomaterials (NM) are attracting significant attention in the field of biomedicine. However, once these nanomaterials are utilized for in vivo treatments they interact with the surrounding physiological environment, leading to the adsorption of various biomolecules onto their surfaces, forming a biomolecular corona (BMC) and thereby influencing the performance and behavior of the nanomaterials. Presently, the in vitro studies of NM primarily involve dispersing the nanoparticles in 10% fetal bovine serum (FBS) and then evaluating their toxicity and therapeutic effects. However, this evaluation method is insufficient as it cannot accurately simulate the conditions of human blood. Moreover, this practical issue remains unresolved to date.

Fig 1. Schematic illustrating the molecular and biological biases arising from the well-known in vitro/in vivo mismatch in nanomedicine due to the biomolecular corona. Reproduced from DOI: 10.1039/D3NH00510K with permission from the Royal Society of Chemistry.

To validate the series of biases existing in established experimental practices and to advance the fields of nanomedicine and nanotoxicology, this study investigated two NM types with vastly different physicochemical properties commonly used in biomedicine. The research compared the molecular and biological biases resulting from the mismatch between NM dispersed in 10% FBS (utilized for in vitro biological assays) and whole human plasma (HP, closer to in vivo administration schemes). Through comparative analysis using proteomics, lipidomics, high-throughput multi-parameter in vitro screening, and single-molecule feature analysis, it was demonstrated that the dynamic changes in BMC composition are material dependent and that cell viability, transport pathways, and autophagic cascades are influenced by the presence or absence of pre-formed BMC corona. These findings underscore the potential limitations of NM in vitro testing in accurately representing real in vivo conditions. Therefore, it is necessary to establish new shared protocols to enhance the accuracy and predictive capability of NM testing.

In summary, this study confirms the biases that may exist when using standard in vitro conditions for NM toxicology assessments, reminding us of the need to establish a comprehensive experimental framework to generate and support new knowledge in the field of biologically relevant nanomaterial interactions. For instance, integrating advanced predictive tools such as artificial intelligence and machine learning will enable nanotoxicology and nanomedicine to progress towards personalized solutions for precision healthcare.

To find out more, please read:

Sources of biases in the in vitro testing of nanomaterials: the role of the biomolecular corona
Valentina Castagnola, Valeria Tomati, Luca Boselli, Clarissa Braccia, Sergio Decherchi, Pier Paolo Pompa, Nicoletta Pedemonte, Fabio Benfenati and Andrea Armirotti
Nanoscale Horiz., 2024, Advance Article

About the blogger

Fangfang Cao is a Research Fellow at National University of Singapore and a member of the Nanoscale Horizons Community Board. Dr Cao’s research focuses on nanocatalytic medicine and microbial therapy.

Face-centered cubic (fcc) metals, such as Au and Ag, usually adopt a packed crystal structure in bulk. However, the equilibrium structure could differ when only a handful of atoms compose a nanocluster. Theories have predicted that particles less than a few nanometers would favor a decahedral packing with a five-fold symmetry; when even fewer atoms are present, say less than two hundred, a 20-fold icosahedral packing would become the lowest-energy configuration. Such fluctuations of the nuclei/seeds may have played a critical role in defining the shape of colloidal nanoparticles in many wet chemical syntheses.

In recent work, a cross-institutional team led by Richard E. Palmer and Thomas J. A. Slater reported the direct observation of such fluctuations on a nearly second-by-second basis. The team synthesized Au nanoclusters containing 309±15 atoms on an amorphous carbon film through mass-selected magnetron sputtering. Subsequently, aberration-corrected scanning transmission electron microscopy (STEM) was employed to track the atomic structures of Au nanoclusters with a frame rate of 0.4–0.7 per second (Fig. 1). To identify the cluster type in each frame, the team compared them to a collection of simulated images with different cluster structures and tilt angles. The clusters exhibited highly dynamic switching between decahedral, icosahedral, and single-crystalline structures under the electron beam, which is sufficiently strong to overcome the energy barriers between such transitions.

Fig. 1 Au309±15 clusters fluctuating under the electron beam. High-angle annular dark field (HAADF) imaging on an aberration-corrected scanning transmission electron microscope (STEM) resolved the atomic structure of these Au nanoclusters frame by frame. Adapted from the supporting data DOI: 10.5281/zenodo.10522408, CC-BY 4.0.

Notably, the authors showed that the Au_309±15 clusters favor the decahedral structure the most, followed by icosahedral and then single-crystalline structures (Fig. 2a). This result is consistent with the probabilities obtained from a snapshot of an ensemble. In theory, the lower-energy structures would have a higher probability of appearance. The ranking of isomeric preferences observed in this study indicates that the cluster size is within a range where the energy ranks in fcc > icosahedral > decahedral (Fig. 2b). Taken together, this work illustrates the possibility of atomic-resolution electron microscopy, when combined with image simulations, to track the isomeric evolution of metal nanoclusters and may shed light on how we understand and regulate nanostructures with atomic precision.

Fig. 1 (a) Histogram of isomer abundances from dynamic movies compared with a static image of a cluster ensemble. Reproduced from DOI: 10.1039/D3NH00291H with permission from the Royal Society of Chemistry. (b) Schematic energy landscape of cluster structures for fcc metals. A red shade indicates the cluster size range in the current study. Ih: icosahedral. Dh: decahedral. Adapted from DOI: 10.1002/anie.202015166 with permission from Wiley-VCH.

To find out more, please read:

Frame-by-frame observations of structure fluctuations in single mass-selected Au clusters using aberration-corrected electron microscopy
Malcolm Dearg, Cesare Roncaglia, Diana Nelli, El Yakout El Koraychy, Riccardo Ferrando, Thomas J. A. Slater, and Richard E. Palmer
Nanoscale Horiz., 2024, 9, 143-147

About the blogger

Jingshan S. Du is a Washington Research Foundation Postdoctoral Fellow at Pacific Northwest National Laboratory and a member of the Nanoscale Horizons Community Board. His research spans crystal formation and transformation pathways, in situ electron microscopy, and hybrid organic/inorganic nanostructures. Du received a Ph.D. in Materials Science and Engineering from Northwestern University in 2021. At Northwestern, he worked on complex nanoparticle systems, correlative electron microscopy of hybrid nanostructures, and nanoscale thermodynamics. Du received a Certificate for Management for Scientists and Engineers from Northwestern’s Kellogg School of Management in 2021 and a B.Sc. in Engineering from Zhejiang University Chu Kochen Honors College in 2015. You can follow him on Twitter @JingshanDu. The views expressed in this article do not necessarily reflect those of the author’s employer or the US government.

In the last few years, immunotherapy has paved new paths for effective treatment of different cancers. Specifically, immunotherapy stimulates T cells, a type of white blood cell called lymphocytes that help to fight germs and destroy tumours. Immunotherapy can be used as a monotherapy or combined with chemotherapy and surgery. Unfortunately, cancer cells and their microenvironment have many sophisticated defence mechanisms that pose considerable challenges to immunotherapy effectiveness and progress. Current strategies to boost cancer immunotherapy include increasing the infiltration of T cells at the tumour site or blocking immune checkpoint-producing immune evasion.

In this regard, an exciting immunotherapy combination approach has been developed by Guixiang Xu and team based on an injectable hydrogel as a carrier to deliver a drug called linagliptin which is capable of inhibiting dipeptidyl peptidases 4 (DPP4) degradation. This leads to prolonged half-life of CXCL10 chemokines and thus, increases recruitment of T cells in the tumour site. Small molecule immune checkpoint blocker (BMS-202) particles were also loaded onto the developed drug carrier to block the programmed cell death-ligand (PD-L1), avoiding immune evasion. The team demonstrated that the application of hydrogel construct (S@LB) suppresses chemokine CXCL10 degradation, increasing T-cell infiltration, while BMS-202 particles inactivate PD-L1 checkpoint in vivo.

Fig. 1 Preparation and mechanism scheme of S@LB. (A) The preparation process of the S@LB solution. (B) Schematic illustration of an injectable hydrogel to reinforce cancer immunotherapy by promoting infiltration of T cells and regulating immune evasion. Reproduced from DOI: 10.1039/D3NH00401E with permission from the Royal Society of Chemistry.

The team tested the in vivo anti-tumour ability, immune response, and lung anti-metastatic effect of the S@LB in combination with chemotactic CXCL10 (S@LB + CXCL10). Their recent report shows that after 18 days of tumour removal, an immune memory effect was detected for the group treated with S@LB + CXCL10.

Overall, this study shows how nano-based hydrogel immunotherapy can be used as an innovative “weapon” against primary and distant tumours, along with efficient inhibition of lung metastasis, indicating tremendous potential for developing transformative clinical applications.

To find out more, please read:

Hydrogel-mediated tumor T cell infiltration and immune evasion to reinforce cancer immunotherapy
Guixiang Xu, Kai Liu, Xiangwu Chen, Yang Lin, Cancan Yu, Xinxin Nie, Wenxiu He, Nathan Karinc and  Yuxia Luan
Nanoscale Horiz., 2024, Advance Article

About the blogger

Susel Del Sol Fernández is a Marie Skłodowska-Curie Postdoctoral fellow at Aragon Nanoscience and Materials Institute (INMA-CSIC), Spain and a member of the Nanoscale Horizons Community Board. Dr Del Sol’s research focuses on designing smart functionalized magnetic nanoparticles for biomedical applications, including magnetic-optical hyperthermia treatment and magnetogenetics. You can follow her on X @SuselDelSol