Nanotoxicity and nanogenotoxicity in cancer therapy mechanisms dual roles and emerging mitigation strategies

Nanomedicine has emerged as a transformative strategy in cancer therapy, enabling precision drug delivery, improved therapeutic efficacy, and personalized treatment paradigms. Despite these advances, clinical translation remains constrained by unresolved nanotoxicity concerns. This minireview critically examines the mechanistic basis of nanoparticle-induced toxicity in oncology, with a particular focus on oxidative stress arising from lysosomal membrane permeabilization, mitochondrial dysfunction, and cytoplasmic redox enzyme dysregulation, which collectively disrupt cellular redox homeostasis and drive excessive reactive oxygen species (ROS) generation. Key ROS-amplifying pathways, including NADPH oxidase activation, redox-sensitive signalling cascades, and Fenton-like reactions associated with metal-based nanoparticles, are highlighted as central mediators of cellular injury. Immune activation and signaling pathway perturbations are discussed in the context of chronic inflammation and altered tumor–immune interactions. The review further addresses nano-genotoxicity as a critical safety endpoint, encompassing DNA strand breaks, chromosomal instability, epigenetic reprogramming, and persistent gene expression alterations. The dualistic nature of nanomedicine is illustrated using representative nanomaterials, including carbon nanotubes (CNTs), which exhibit high drug-loading capacity alongside documented genotoxic and oxidative liabilities, and cerium oxide nanoparticles, whose antioxidant or cytotoxic behavior is dictated by physicochemical properties and intracellular context. Strategies to mitigate nanotoxicity are discussed, including surface functionalization, biocompatible coatings, biodegradable nanocarriers, and mechanism-informed toxicity screening approaches aligned with regulatory expectations. Finally, emerging directions are outlined, emphasizing artificial intelligence–assisted nanotoxicity prediction, computational modeling of nano–bio interactions, standardized safety assessment frameworks, and interdisciplinary collaboration as critical enablers of safe clinical translation. These insights support the rational design of safer nanomedicines and reinforce the need for mechanistic toxicology to guide their development for cancer care.