The field of nanotechnology has experienced significant growth, with nanoparticles (NPs) and nanoconstructs finding diverse applications, especially in the medical field. These materials, due to their unique physical and chemical properties, have considerable potential in improving both diagnostic and therapeutic approaches, particularly in oncology. However, as engineered nanomaterials (ENMs) are increasingly used, concerns about their safety and potential toxicity have emerged, emphasizing the need for comprehensive safety assessments. Core-shell nanoconstructs, which are composed of nanoparticles and surface-modifying ligands, are designed to improve the precision and efficiency of drug delivery. These constructs are capable of specifically targeting disease sites, overcoming issues often encountered in cancer treatments, such as off-target effects, uncontrolled drug release, and high toxicity. While these advantages are promising, the use of nanoconstructs also presents challenges, particularly in ensuring accurate delivery and refining their design through advanced computational modeling. Additionally, the behavior of these nanomaterials in biological systems can be unpredictable and highly dependent on factors such as size, surface chemistry, and the method of synthesis. In vitro toxicity studies often fail to simulate the actual effects seen in vivo, which underlines the necessity for standardized testing protocols to assess their safety more reliably. A collaborative, multidisciplinary approach involving toxicologists, biologists, and engineers is crucial to overcoming these challenges. This will help to deepen the understanding of nanoconstructs’ interactions with biological systems and ensure their safe integration into medical practice.