Nanodrugs hold great promise for targeted therapies, but their potential for cytotoxicity remains a major area of concern, threatening both patient safety and clinical translation. In this systematic review, we conducted a systematic investigation of nanotoxicity studies-identified through an AI-assisted screening procedure using Scopus, PubMed, and Elicit AI-to establish the molecular determinants of nanodrug-induced cytotoxicity. Our findings reveal three dominant and linked mechanisms that consistently act in a range of nanomaterials: oxidative stress, inflammatory signaling, and lysosomal disruption. Key nanomaterial properties like chemical structure, size, shape, surface charge, tendency to aggregate, and biocorona formation control these pathways, modulating cellular uptake, reactive oxygen species generation, cytokine release, and subcellular injury. Notably, the most frequent mechanism was oxidative stress, which often initiated downstream inflammatory and apoptotic signaling. By linking these toxicity pathways with particular nanoparticle characteristics, our review presents necessary guidelines for safer, more biocompatible nanodrug formulation design. This extensive framework acknowledges the imperative necessity for mechanistic toxicity assessment in nanopharmaceutical design and underscores the strength of AI tools in driving systematic toxicology studies.

• Keywords
• ROS, cytotoxicity, molecular mechanisms of nanotoxicity, nanodrugs, nanoparticles, oxidative stress,
• MeSH
• Apoptosis drug effects   MeSH
• Humans MeSH
• Lysosomes drug effects   metabolism   MeSH
• Nanoparticles * chemistry   toxicity   MeSH
• Nanostructures * toxicity   chemistry   MeSH
• Oxidative Stress drug effects   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH
• Names of Substances
• Reactive Oxygen Species 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
• Actins metabolism   chemistry   MeSH
• Cytoskeleton * metabolism   chemistry   MeSH
• DNA * chemistry   metabolism   MeSH
• Humans MeSH
• Actin Cytoskeleton * metabolism   chemistry   MeSH
• Nanostructures * chemistry   MeSH
• Surface Properties MeSH
• Particle Size MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Actins MeSH
• DNA * MeSH

DNA nanotechnology has emerged as a groundbreaking field, using DNA as a scaffold to create nanostructures with customizable properties. These DNA nanostructures hold potential across various domains, from biomedicine to studying ionizing radiation-matter interactions at the nanoscale. This review explores how the various types of radiation, covering a spectrum from electrons and photons at sub-excitation energies to ion beams with high-linear energy transfer influence the structural integrity of DNA origami nanostructures. We discuss both direct effects and those mediated by secondary species like low-energy electrons (LEEs) and reactive oxygen species (ROS). Further we discuss the possibilities for applying radiation in modulating and controlling structural changes. Based on experimental insights, we identify current challenges in characterizing the responses of DNA nanostructures to radiation and outline further areas for investigation. This review not only clarifies the complex dynamics between ionizing radiation and DNA origami but also suggests new strategies for designing DNA nanostructures optimized for applications exposed to various qualities of ionizing radiation and their resulting byproducts.

• Keywords
• DNA damage, DNA structures, Nanostructures, Nanotechnology,
• MeSH
• DNA * chemistry   MeSH
• Electrons MeSH
• Radiation, Ionizing MeSH
• Nucleic Acid Conformation radiation effects   MeSH
• Nanostructures * chemistry   MeSH
• Nanotechnology * MeSH
• Reactive Oxygen Species chemistry   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• DNA * MeSH
• Reactive Oxygen Species 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.

• Keywords
• DNA nanotechnology, Interferon, Lysosomal rupture, Nanotechnology, bio/nano interactions, lysosome interference,
• Publication type
• Journal Article MeSH

It has become evident that physical stimuli of the cellular microenvironment transmit mechanical cues regulating key cellular functions, such as proliferation, migration, and malignant transformation. Accumulating evidence suggests that tumor cells face variable mechanical stimuli that may induce metabolic rewiring of tumor cells. However, the knowledge of how tumor cells adapt metabolism to external mechanical cues is still limited. We therefore designed soft 3D collagen scaffolds mimicking a pathological mechanical environment to decipher how liver tumor cells would adapt their metabolic activity to physical stimuli of the cellular microenvironment. Here, we report that the soft 3D microenvironment upregulates the glycolysis of HepG2 and Alexander cells. Both cell lines adapt their mitochondrial activity and function under growth in the soft 3D microenvironment. Cells grown in the soft 3D microenvironment exhibit marked mitochondrial depolarization, downregulation of mitochondrially encoded cytochrome c oxidase I, and slow proliferation rate in comparison with stiff monolayer cultures. Our data reveal the coupling of liver tumor glycolysis to mechanical cues. It is proposed here that soft 3D collagen scaffolds can serve as a useful model for future studies of mechanically regulated cellular functions of various liver (potentially other tissues as well) tumor cells.

• Keywords
• cancer, cell plasticity, cytoskeleton, engineered cell microenvironments, extracellular matrix, mechanical forces, mitochondria,
• MeSH
• Collagen MeSH
• Humans MeSH
• Mitochondrial Dynamics MeSH
• Tumor Microenvironment * MeSH
• Liver Neoplasms * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Collagen MeSH

DNA nanotechnology has yielded remarkable advances in composite materials with diverse applications in biomedicine. The specificity and predictability of building 3D structures at the nanometer scale make DNA nanotechnology a promising tool for uses in biosensing, drug delivery, cell modulation, and bioimaging. However, for successful translation of DNA nanostructures to real-world applications, it is crucial to understand how they interact with living cells, and the consequences of such interactions. In this review, we summarize the current state of knowledge on the interactions of DNA nanostructures with cells. We identify key challenges, from a cell biology perspective, that influence progress towards the clinical translation of DNA nanostructures. We close by providing an outlook on what questions must be addressed to accelerate the clinical translation of DNA nanostructures. STATEMENT OF SIGNIFICANCE: Self-assembled DNA nanostructures (DNs) offers unique opportunities to overcome persistent challenges in the nanobiotechnology field. However, the interactions between engineered DNs and living cells are still not well defined. Critical systematization of current cellular models and biological responses triggered by DNs is a crucial foundation for the successful clinical translation of DNA nanostructures. Moreover, such an analysis will identify the pitfalls and challenges that are present in the field, and provide a basis for overcoming those challenges.

• Keywords
• Bionano interactions, Cellular uptake, Cytotoxicity, DNA nanotechnology, Nanotechnology, Protein corona,
• MeSH
• DNA chemistry   MeSH
• Drug Delivery Systems methods   MeSH
• Nanostructures * chemistry   MeSH
• Nanotechnology methods   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• DNA MeSH