Toxicity of nanostructures in drug delivery applications.

Nanostructures and nanoparticles have transformed drug delivery by enabling enhanced bioavailability, targeted therapy, controlled drug release, and improved therapeutic outcomes; however, these benefits come with complex safety and translational challenges that remain incompletely resolved. This updated review synthesizes recent advances in nanostructured drug carriers over the past five years, emphasizing unique delivery platforms such as engineered exosomes, transfersomes, cubosomes, and solid lipid nanoparticles (SLNs), and discusses their mechanisms of action, disease-specific applications, and emerging toxicity insights (e.g., neurotoxicity, pulmonary toxicity, and reproductive toxicity), which are often overlooked. Exosomes, as natural extracellular vesicles, exemplify a class of multifunctional nanocarriers that can encapsulate diverse therapeutic payloads with low inherent toxicity and favorable pharmacokinetics, and recent engineering approaches such as microfluidics, lipid modification, and surface ligand decoration have advanced their targeting precision and clinical potential, particularly for challenging indications like central nervous system infections via blood-brain barrier penetration. Moreover, this review incorporates analytical discussion of specific biological pathways and biomarkers associated with nanostructure toxicity including reactive oxygen species (ROS)-driven oxidative stress, lysosomal dysfunction, immune activation, and organ accumulation and quantitatively evaluates risk indicators across different nanocarrier classes, addressing gaps in dose, exposure duration, and aggregation state effects. Regulatory contexts and advanced predictive toxicology models, including artificial intelligence-guided quantitative structure-activity relationship (QSAR) and physiologically based pharmacokinetic (PBPK) simulations, are critically evaluated for their roles in regulatory decision-making and clinical translation. By integrating recent high-impact literature and methodical toxicity frameworks with detailed mechanistic insights, this review offers a comprehensive and up-to-date resource that delineates both therapeutic innovation and safety considerations in nanostructure-based drug delivery.