New insights into the toxicity of lanthanides with functional genomics.

As the use of lanthanides increases in many industries, concerns regarding their impact on human health rise. However, until recently, the toxicological profile of these elements had been incompletely characterized, with most studies relying on biodistribution assessments and lethal dose determinations in different animal models. In the last few years, the f-element field has started to pivot towards other examination types that identify cellular and molecular mechanisms of toxicity in a high-throughput manner. Under this new paradigm, functional genomics techniques, which rely on genetically modified cells or model organisms with missing genes or proteins, are becoming fundamental to gain novel insights into the genetic and proteomic bases of lanthanide toxicity, as well as to identify potential therapeutic targets to minimize the harmful effects of the metals. This review aims to provide an updated perspective on current efforts using functional genomics to characterize the toxicity and biological impact of lanthanides and improve their safety in different industrial applications.

Clinical translation and landscape of silver nanoparticles.

Despite being clinically used for over a century, the benefits of silver nanoparticles are perennially under debate and dispute. In the last two decades, a revived interest in their therapeutic applications has resulted in a few new formulations transitioning into clinical trials. These metal nanomedicines are used in concrete applications that are defined by the physicochemical and biological features of the silver nanoconstructs, as well as their biodistribution profiles. Examples of these applications are topical antibacterial and antiviral therapies and wound healing, as these avoid concerns regarding the long-term accumulation of the nanomedicines in fenestrated organs after intravenous administration. Here, we discuss the current landscape of silver nanoparticles, and critically analyze the characteristics that endowed their transition and use in clinical settings.

Polymeric antibubbles with strong ultrasound imaging capabilities.

Antibubbles are liquid droplets encapsulated by a gas film that have recently been explored for on-demand ultrasound-triggered drug release. However, their ultrasound imaging capabilities are limited by their stiff shells stabilized with silica nanoparticles. Here, we develop polymeric antibubbles that generate greater ultrasound contrast than silica-based antibubbles, while showing better stability than conventional polymeric microbubbles.

Assessing inorganic nanoparticle toxicity through omics approaches.

In the last two decades, the development of nanotechnology has resulted in inorganic nanoparticles playing crucial roles in key industries, ranging from healthcare to energy technologies. For instance, gold and silver nanoparticles are widely used in rapid COVID-19 and flu tests, titania and zinc oxide nanoparticles are commonly found in cosmetic products, and superparamagnetic iron oxide nanoparticles have been clinically exploited as contrast agents and anti-anemia medicines. As a result, human exposure to nanomaterials is continuously increasing, raising concerns about their potential adverse health effects. Historically, the study of nanoparticle toxicity has largely relied on macroscopic observations obtained in different in vitro and in vivo models, resulting in readouts such as median lethal dose, biodistribution profile, and/or histopathological assessment. In recent years, omics methodologies, including transcriptomics, epigenomics, proteomics, metabolomics, and lipidomics, are increasingly used to characterize the biological interactions of nanomaterials, providing a better and broader understanding of their impact and mechanisms of toxicity. These approaches have been able to identify important genes and gene products that mediate toxicological effects, as well as endogenous functions and pathways dysregulated by nanoparticles. Omics methods improve our understanding of nanoparticle biology, and unravel mechanistic insights into nanomedicine-based therapies. This review aims to provide a deeper understanding and new perspectives of omics approaches to characterize the toxicity and biological interactions of inorganic nanoparticles, and improve the safety of nanoparticle applications.

Improving MPI and hyperthermia performance of superparamagnetic iron oxide nanoparticles through fractional factorial design of experiments.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used for biomedical applications, including magnetic particle imaging (MPI) and magnetic hyperthermia. The co-precipitation method is one of the most common synthetic routes to obtain SPIONs, since it is simple and does not require extreme conditions, such as high temperatures. Despite its prevalence, however, the co-precipitation synthesis presents some challenges, most notably the high batch-to-batch variability, as multiple factors can influence nanoparticle growth. In this study, we utilized a fractional factorial design of experiments to identify key factors influencing SPION growth, properties, and performance in MPI and magnetic hyperthermia, namely Fe3+ content, pH, temperature, stirring, and atmosphere. Notably, our study unveiled secondary interactions, particularly between temperature and Fe3+ content, as well as pH and Fe3+ content, for which simultaneous changes of both parameters promoted greater effects than the sum of each factor effect alone, emphasizing the impact of synergistic effects on SPION growth and performance. These findings provide a deeper understanding of the growth mechanism of SPIONs, reconcile discrepancies in the existing literature, and underscore the importance of characterizing secondary interactions to improve the performance of SPIONs for biomedical applications.

Polymeric Microbubble Shell Engineering: Microporosity as a Key Factor to Enhance Ultrasound Imaging and Drug Delivery Performance.

Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer-mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA-based MB products, facilitating the potential translation of next-generation PBCA MB.

Differentiation of different dibenzothiophene (DBT) desulfurizing bacteria via surface-enhanced Raman spectroscopy (SERS).

Fossil fuels are considered vital natural energy resources on the Earth, and sulfur is a natural component present in them. The combustion of fossil fuels releases a large amount of sulfur in the form of SO x in the atmosphere. SO x is the major cause of environmental problems, mainly air pollution. The demand for fuels with ultra-low sulfur is growing rapidly. In this aspect, microorganisms are proven extremely effective in removing sulfur through a process known as biodesulfurization. A major part of sulfur in fossil fuels (coal and oil) is present in thiophenic structures such as dibenzothiophene (DBT) and substituted DBTs. In this study, the identification and characterization of DBT desulfurizing bacteria (Chryseobacterium sp. IS, Gordonia sp. 4N, Mycolicibacterium sp. J2, and Rhodococcus sp. J16) based on their specific biochemical constituents were conducted using surface-enhanced Raman spectroscopy (SERS). By differentiating DBT desulfurizing bacteria, researchers can gain insights into their unique characteristics, thus leading to improved biodesulfurization strategies. SERS was used to differentiate all these species based on their biochemical differences and different SERS vibrational bands, thus emerging as a potential technique. Moreover, multivariate data analysis techniques such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were employed to differentiate these DBT desulfurizing bacteria on the basis of their characteristic SERS spectral signals. For all these isolates, the accuracy, sensitivity, and specificity are above 90%, and an AUC (area under the curve) value of close to 1 was achieved for all PLS-DA models.

SERS characterization of biochemical changes associated with biodesulfurization of dibenzothiophene using Gordonia sp. HS126-4N.

In this study, Gordonia sp. HS126-4N was employed for dibenzothiophene (DBT) biodesulfurization, tracked over 9 days using SERS. During the initial lag phase, no significant spectral changes were observed, but after 48 h, elevated metabolic activity was evident. At 72 h, maximal bacterial population correlated with peak spectrum variance, followed by stable spectral patterns. Despite 2-hydroxybiphenyl (2-HBP) induced enzyme suppression, DBT biodesulfurization persisted. PCA and PLS-DA analysis of the SERS spectra revealed distinctive features linked to both bacteria and DBT, showcasing successful desulfurization and bacterial growth stimulation. PLS-DA achieved a specificity of 95.5 %, sensitivity of 94.3 %, and AUC of 74 %, indicating excellent classification of bacteria exposed to DBT. SERS effectively tracked DBT biodesulfurization and bacterial metabolic changes, offering insights into biodesulfurization mechanisms and bacterial development phases. This study highlights SERS' utility in biodesulfurization research, including its use in promising advancements in the field.

Nanoscale engineering of gold nanostars for enhanced photoacoustic imaging.

Photoacoustic (PA) imaging is a diagnostic modality that combines the high contrast resolution of optical imaging with the high tissue penetration of ultrasound. While certain endogenous chromophores can be visualized via PA imaging, many diagnostic assessments require the administration of external probes. Anisotropic gold nanoparticles are particularly valued as contrast agents, since they produce strong PA signals and do not photobleach. However, the synthesis of anisotropic nanoparticles typically requires cytotoxic reagents, which can hinder their biological application. In this work, we developed new PA probes based on nanostar cores and polymeric shells. These AuNS were obtained through one-pot synthesis with biocompatible Good's buffers, and were subsequently functionalized with polyethylene glycol, chitosan or melanin, three coatings widely used in (pre)clinical research. Notably, the structural features of the nanostar cores strongly affected the PA signal. For instance, despite displaying similar sizes (i.e. 45 nm), AuNS obtained with MOPS buffer generated between 2 and 3-fold greater signal intensities in the region between 700 and 800 nm than nanostars obtained with HEPES and EPPS buffers, and up to 25-fold stronger signals than spherical gold nanoparticles. A point source analytical model demonstrated that AuNS synthesized with MOPS displayed greater absorption coefficients than the other particles, corroborating the stronger PA responses. Furthermore, the AuNS shell not only improved the biocompatibility of the nanoconstructs but also affected their performance, with melanin coating enhancing the signal more than 4-fold, due to its own PA capacity, as demonstrated by both in vitro and ex vivo imaging. Taken together, these results highlight the strengths of gold nanoconstructs as PA probes and offer insights into the design rules for the nanoengineering of new nanodiagnostic agents.

Hybrid ultrasound and photoacoustic contrast agent designs combining metal phthalocyanines and PBCA microbubbles.

Photoacoustic (PA) imaging is an emerging diagnostic technology that combines the penetration depth of ultrasound (US) imaging and the contrast resolution of optical imaging. Although PA imaging can visualize several endogenous chromophores to obtain clinically-relevant information, multiple applications require the administration of external contrast agents. Metal phthalocyanines have strong PA properties and chemical stability, but their extreme hydrophobicity requires their encapsulation in delivery systems for biomedical applications. Hence, we developed hybrid US/PA contrast agents by encapsulating metal phthalocyanines in poly(butyl cyanoacrylate) microbubbles (PBCA MB), which display acoustic response and ability to efficiently load hydrophobic drugs. Six different metal chromophores were loaded in PBCA MB, showing greater encapsulation efficiency with higher chromophore hydrophobicity. Notably, while the US response of the MB was unaffected by the loading of the chromophores, the PA characteristics varied greatly. Among the different formulations, MB loaded with zinc and cobalt naphthalocyanines showed the strongest PA contrast, as a result of high encapsulation efficiencies and tunable optical properties. The strong US and PA contrast signals of the formulations were preserved in biological environment, as demonstrated by in vitro imaging in serum and whole blood, and ex vivo imaging in deceased mice. Taken together, these findings highlight the advantages of combining highly hydrophobic PA contrast agents and polymeric MB for the development of contrast agents for hybrid US/PA imaging, where different types of information (structural, functional, or potentially molecular) can be acquired by combining both imaging modalities.

Role of Surface Curvature in Gold Nanostar Properties and Applications.

Gold nanostars (AuNSs) are nanoparticles with intricate three-dimensional structures and shape-dependent optoelectronic properties. For example, AuNSs uniquely display three distinct surface curvatures, i.e. neutral, positive, and negative, which provide different environments to adsorbed ligands. Hence, these curvatures are used to introduce different surface chemistries in nanoparticles. This review summarizes and discusses the role of surface curvature in AuNS properties and its impact on biomedical and chemical applications, including surface-enhanced Raman spectroscopy, contrast agent performance, and catalysis. We examine the main synthetic approaches to generate AuNSs, control their morphology, and discuss their benefits and drawbacks. We also describe the optical characteristics of AuNSs and discuss how these depend on nanoparticle morphology. Finally, we analyze how AuNS surface curvature endows them with properties distinctly different from those of other nanoparticles, such as strong electromagnetic fields at the tips and increased hydrophilic environments at the indentations, together making AuNSs uniquely useful for biosensing, imaging, and local chemical manipulation.

Transferrin Receptor-Targeted Nonspherical Microbubbles for Blood-Brain Barrier Sonopermeation.

Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer-based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US-mediated blood-brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface-modified with BBB-specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod-shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti-TfR-MB bind more efficiently to BBB endothelium than spherical anti-TfR-MB, both in vitro and in vivo. BBB-associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB-targeted MB. These findings exemplify the potential of antibody-modified nonspherical MB for targeted and triggered drug delivery to the brain.

Polymeric materials for ultrasound imaging and therapy.

Ultrasound (US) is routinely used for diagnostic imaging and increasingly employed for therapeutic applications. Materials that act as cavitation nuclei can improve the resolution of US imaging, and facilitate therapeutic US procedures by promoting local drug delivery or allowing temporary biological barrier opening at moderate acoustic powers. Polymeric materials offer a high degree of control over physicochemical features concerning responsiveness to US, e.g. via tuning chain composition, length and rigidity. This level of control cannot be achieved by materials made of lipids or proteins. In this perspective, we present key engineered polymeric materials that respond to US, including microbubbles, gas-stabilizing nanocups, microcapsules and gas-releasing nanoparticles, and discuss their formulation aspects as well as their principles of US responsiveness. Focusing on microbubbles as the most common US-responsive polymeric materials, we further evaluate the available chemical toolbox to engineer polymer shell properties and enhance their performance in US imaging and US-mediated drug delivery. Additionally, we summarize emerging applications of polymeric microbubbles in molecular imaging, sonopermeation, and gas and drug delivery, based on refinement of MB shell properties. Altogether, this manuscript provides new perspectives on US-responsive polymeric designs, envisaging their current and future applications in US imaging and therapy.

Screening the complex biological behavior of late lanthanides through genome-wide interactions.

Despite their similar physicochemical properties, recent studies have demonstrated that lanthanides can display different biological behaviors. Hence, the lanthanide series can be divided into three parts, namely early, mid, and late lanthanides, based on their interactions with biological systems. In particular, the late lanthanides demonstrate distinct, but poorly understood biological activity. In the current study, we employed genome-wide functional screening to help understand biological effects of exposure to Yb(III) and Lu(III), which were selected as representatives of the late lanthanides. As a model organism, we used Saccharomyces cerevisiae, since it shares many biological functions with humans. Analysis of the functional screening results indicated toxicity of late lanthanides is consistent with disruption of vesicle-mediated transport, and further supported a role for calcium transport processes and mitophagy in mitigating toxicity. Unexpectedly, our analysis suggested that late lanthanides target proteins with SH3 domains, which may underlie the observed toxicity. This study provides fundamental insights into the unique biological chemistry of late lanthanides, which may help devise new avenues toward the development of decorporation strategies and bio-inspired separation processes.

Nonspherical ultrasound microbubbles.

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

Clinical translation of gold nanoparticles.

Gold nanoparticles display unique physicochemical features, which can be useful for therapeutic purposes. After two decades of preclinical progress, gold nanoconstructs are slowly but steadily transitioning into clinical trials. Although initially thought to be "magic golden bullets" that could be used to treat a wide range of diseases, current consensus has moved toward a more realistic approach, where gold nanoformulations are being investigated to treat specific disorders. These therapeutic applications are dictated by the pharmacokinetics and biodistribution profiles of gold nanoparticles. Here, we analyze the current clinical landscape of therapeutic gold nanoconstructs, discuss the shared characteristics that allowed for their transition from bench to bedside, and examine existing hurdles that need to be overcome before they can be approved for clinical use.

Enhanced Stable Cavitation and Nonlinear Acoustic Properties of Poly(butyl cyanoacrylate) Polymeric Microbubbles after Bioconjugation.

Microbubbles (MB) are used as ultrasound (US) contrast agents in clinical settings because of their ability to oscillate upon exposure to acoustic pulses and generate nonlinear responses with a stable cavitation profile. Polymeric MB have recently attracted increasing attention as molecular imaging probes and drug delivery agents based on their tailorable acoustic responses, high drug loading capacity, and surface functionalization capabilities. While many of these applications require MB to be functionalized with biological ligands, the impact of bioconjugation on polymeric MB cavitation and acoustic properties remains poorly understood. Hence, we here evaluated the effects of MB shell hydrolysis and subsequent streptavidin conjugation on the acoustic behavior of poly(butyl cyanoacrylate) (PBCA) MB. We show that upon biofunctionalization, MB display higher acoustic stability, stronger stable cavitation, and enhanced second harmonic generation. Furthermore, functionalized MB preserve the binding capabilities of streptavidin conjugated on their surface. These findings provide insights into the effects of bioconjugation chemistry on polymeric MB acoustic properties, and they contribute to improving the performance of polymer-based US imaging and theranostic agents.

Nanoparticle Diagnostics and Theranostics in the Clinic.

Nanoparticles possess unique features that may be useful for disease diagnosis and therapy. Preclinically, many different nanodiagnostics have been explored, but only a few have made it to the market. We here provide an overview of nanoparticle-based imaging agents currently used and evaluated in the clinic and discuss preclinical progress and translational avenues for the use of nanoparticles for diagnostic and theranostic applications.