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 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.

• Publication type
• Journal Article MeSH
• Review MeSH