Therapeutic potential and toxicological challenges of metal nanoparticles in drug delivery: A comprehensive review

Abstract

Metal nanoparticles (NPs) have emerged as advanced drug delivery systems, combining high therapeutic potential with complex safety considerations. Their unique physicochemical features, including high surface-to-volume ratios, tunable surfaces, and the ability to cross biological barriers, enable applications in targeted drug delivery and theranostics. Gold (Au), silver (Ag), iron oxide (Fe₃O₄), zinc oxide (ZnO), and platinum (Pt) NPs demonstrate outstanding efficacy: AuNPs achieve >90 % drug loading and 3–5× improved tumour targeting, AgNPs show up to 99 % antimicrobial activity, and Fe₃O₄ NPs function as both drug carriers and MRI contrast agents. However, toxicity remains a major hurdle. Reported challenges include dose-dependent cytotoxicity (IC₅₀: 10–40 μg/mL), hepatic retention (30–40 %), oxidative stress (2–10× ROS increase), and immune activation (up to 3-fold cytokine elevation). Safety is governed by physicochemical properties, with <10 nm NPs showing efficient penetration but higher genotoxicity, and cationic surfaces being 2–3× more cytotoxic. Several strategies have been developed to overcome these barriers. PEGylation reduces macrophage uptake by 60–75 % and extends circulation time, biodegradable hybrids reduce long-term accumulation by 70–80 %, and controlled-release systems cut doses by 30–50 % without compromising efficacy. Advances in computational tools, such as machine learning (~87 % predictive accuracy), along with standardized testing (<20 % variability), have accelerated preclinical evaluation by 40–50 %. These improvements contribute to therapeutic indices >10 and Phase I trial success rates of 65–75 %, significantly outperforming first-generation nanocarriers. This review highlights the need for multidisciplinary integration of nanotechnology, toxicology, computational modelling, and regulatory frameworks. With continued innovation, metal NPs hold the potential to revolutionize precision medicine through safer, scalable, and clinically translatable nanoplatforms.