Nanodiamonds (NDs) display several attractive features rendering them useful for medical applications such as drug delivery. However, the interactions between NDs and the immune system remain poorly understood. Here, we investigated amino-, carboxyl-, and poly(ethylene glycol) (PEG)-terminated NDs with respect to primary human immune cells. We applied cytometry by time-of-flight (CyToF) to assess the impact on peripheral blood mononuclear cells at the single-cell level, and observed an expansion of plasmacytoid dendritic cells (pDCs) which are critically involved in antiviral responses. Subsequent experiments demonstrated that the NDs were actively internalized, leading to a vigorous type I interferon response involving endosomal Toll-like receptors. ND-NH2 and ND-COOH were more potent than ND-PEG, as evidenced by using TLR reporter cell lines. Computational studies demonstrated that NDs interacted with the ligand-binding domains of TLR7 and TLR9 with high affinity though this was less pronounced for ND-PEG. NDs with varying surface functionalities were also readily taken up by macrophages. To gain further insight, we performed RNA sequencing of a monocyte-like cell line exposed to NDs, and found that the phagosome maturation pathway was significantly affected. Indeed, evidence for lysosomal hyperacidification was obtained in dendritic cells and macrophages exposed to NDs. Moreover, using a reporter cell line, NDs were found to impinge on autophagic flux. However, NDs did not affect viability of any of the cell types studied. This study has shown that NDs subvert dendritic cells leading to an antiviral-like immune response. This has implications not only for drug delivery but also for anticancer vaccines using NDs.

• Klíčová slova
• autophagy, dendritic cells, interferon, macrophages, nanodiamonds,
• MeSH
• dendritické buňky * účinky léků   imunologie   metabolismus   MeSH
• interferon typ I * MeSH
• interferony * metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• makrofágy * účinky léků   imunologie   metabolismus   MeSH
• nanodiamanty * chemie   MeSH
• polyethylenglykoly chemie   MeSH
• toll-like receptor 7 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interferon typ I * MeSH
• interferony * MeSH
• nanodiamanty * MeSH
• polyethylenglykoly MeSH
• toll-like receptor 7 MeSH

DNA nanotechnology has revolutionized materials science and biomedicine by enabling precise manipulation of matter at the nanoscale. DNA nanostructures (DNs) in particular represent a promising frontier for targeted therapeutics. Engineered DNs offer unprecedented molecular programmability, biocompatibility, and structural versatility, making them ideal candidates for advanced drug delivery, organelle regulation, and cellular function modulation. This Perspective explores the emerging role of DNs in modulating cellular behavior through organelle-targeted interventions. We highlight current advances in nuclear, mitochondrial, and lysosomal targeting, showcasing applications ranging from gene delivery to cancer therapeutics. For instance, DNs have enabled precision mitochondrial disruption in cancer cells, lysosomal pH modulation to enhance gene silencing, and nuclear delivery of gene-editing templates. While DNs hold immense promise for advancing nanomedicine, outstanding challenges include optimizing biological interactions and addressing safety concerns. This Perspective highlights the current potential of DNs for rational control of targeted organelles, which could lead to novel therapeutic strategies and advancement of precision nanomedicines in the future.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

DNA nanostructures (DNs) have gained popularity in various biomedical applications due to their unique properties, including structural programmability, ease of synthesis and functionalization, and low cytotoxicity. Effective utilization of DNs in biomedical applications requires a fundamental understanding of their interactions with living cells and the mechanics of cellular uptake. Current knowledge primarily focuses on how the physicochemical properties of DNs, such as mass, shape, size, and surface functionalization, affect uptake efficacy. However, the role of cellular mechanics and morphology in DN uptake remains largely unexplored. In this work, we show that cells subjected to geometric constraints remodel their actin cytoskeleton, resulting in differential mechanical force generation that facilitates DN uptake. The length, number, and orientation of F-actin fibers are influenced by these constraints, leading to distinct mechanophenotypes. Overall, DN uptake is governed by F-actin forces arising from filament reorganisation under geometric constraints. These results underscore the importance of actin dynamics in the cellular uptake of DNs and suggest that leveraging geometric constraints to induce specific cell morphology adaptations could enhance the uptake of therapeutically designed DNs.

• MeSH
• aktiny metabolismus   chemie   MeSH
• cytoskelet * metabolismus   chemie   MeSH
• DNA * chemie   metabolismus   MeSH
• lidé MeSH
• mikrofilamenta * metabolismus   chemie   MeSH
• nanostruktury * chemie   MeSH
• povrchové vlastnosti MeSH
• velikost částic MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aktiny MeSH
• DNA * MeSH

DNA nanotechnology is a rapidly growing field that provides exciting tools for biomedical applications. Targeting lysosomal functions with nanomaterials, such as DNA nanostructures (DNs), represents a rational and systematic way to control cell functionality. Here we present a versatile DNA nanostructure-based platform that can modulate a number of cellular functions depending on the concentration and surface decoration of the nanostructure. Utilizing different peptides for surface functionalization of DNs, we were able to rationally modulate lysosomal activity, which in turn translated into the control of cellular function, ranging from changes in cell morphology to modulation of immune signaling and cell death. Low concentrations of decalysine peptide-coated DNs induced lysosomal acidification, altering the metabolic activity of susceptible cells. In contrast, DNs coated with an aurein-bearing peptide promoted lysosomal alkalization, triggering STING activation. High concentrations of decalysine peptide-coated DNs caused lysosomal swelling, loss of cell-cell contacts, and morphological changes without inducing cell death. Conversely, high concentrations of aurein-coated DNs led to lysosomal rupture and mitochondrial damage, resulting in significant cytotoxicity. Our study holds promise for the rational design of a new generation of versatile DNA-based nanoplatforms that can be used in various biomedical applications, like the development of combinatorial anti-cancer platforms, efficient systems for endolysosomal escape, and nanoplatforms modulating lysosomal pH.

• Klíčová slova
• DNA nanotechnology, Interferon, Lysosomal rupture, Nanotechnology, bio/nano interactions, lysosome interference,
• Publikační typ
• časopisecké články MeSH

In recent years, it has been recognized that mechanical forces play an important regulative role in living organisms and possess a direct impact on crucial cell functions, ranging from cell growth to maintenance of tissue homeostasis. Advancements in mechanobiology have revealed the profound impact of mechanical signals on diverse cellular responses that are cell type specific. Notably, numerous studies have elucidated the pivotal role of different mechanical cues as regulatory factors influencing various cellular processes, including cell spreading, locomotion, differentiation, and proliferation. Given these insights, it is unsurprising that the responses of cells regulated by physical forces are intricately linked to the modulation of nanoparticle uptake kinetics and processing. This complex interplay underscores the significance of understanding the mechanical microenvironment in shaping cellular behaviors and, consequently, influencing how cells interact with and process nanoparticles. Nevertheless, our knowledge on how localized physical forces affect the internalization and processing of nanoparticles by cells remains rather limited. A significant gap exists in the literature concerning a systematic analysis of how mechanical cues might bias the interactions between nanoparticles and cells. Hence, our aim in this review is to provide a comprehensive and critical analysis of the existing knowledge regarding the influence of mechanical cues on the complicated dynamics of cell-nanoparticle interactions. By addressing this gap, we would like to contribute to a detailed understanding of the role that mechanical forces play in shaping the complex interplay between cells and nanoparticles.

• Klíčová slova
• Extracellular matrix, Mechanical cues, Mechanotransduction, Nanomedicine; Nanoparticles,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Iron oxide nanoparticles (IONPs) are being actively researched in various biomedical applications, particularly as magnetic resonance imaging (MRI) contrast agents for diagnosing various liver pathologies like nonalcoholic fatty liver diseases, nonalcoholic steatohepatitis, and cirrhosis. Emerging evidence suggests that IONPs may exacerbate hepatic steatosis and liver injury in susceptible livers such as those with nonalcoholic fatty liver disease. However, our understanding of how IONPs may affect steatotic cells at the sub-cellular level is still fragmented. Generally, there is a lack of studies identifying the molecular mechanisms of potential toxic and/or adverse effects of IONPs on "non-heathy" in vitro models. In this study, we demonstrate that IONPs, at a dose that does not cause general toxicity in hepatic cells (Alexander and HepG2), induce significant toxicity in steatotic cells (cells loaded with non-toxic doses of palmitic acid). Mechanistically, co-treatment with PA and IONPs resulted in endoplasmic reticulum (ER) stress, accompanied by the release of cathepsin B from lysosomes to the cytosol. The release of cathepsin B, along with ER stress, led to the activation of apoptotic cell death. Our results suggest that it is necessary to consider the interaction between IONPs and the liver, especially in susceptible livers. This study provides important basic knowledge for the future optimization of IONPs as MRI contrast agents for various biomedical applications.

• Publikační typ
• časopisecké články MeSH