What is actually “gold-specific” in gold nanoparticles for drug delivery and anticancer applications?

 

Gold nanoparticles (AuNPs) are widely studied as drug delivery platforms and as candidates for cancer therapy. However, surface modification and drug loading are possible with many nanocarriers, including liposomes, polymeric nanoparticles, silica nanoparticles, and hybrid systems. What distinguishes AuNPs is the particular combination of surface chemistry, optical properties, structural tunability, and platform stability that gold provides.

Gold-specific features in drug delivery

A major practical advantage of AuNPs is the ease of surface functionalization. Gold forms strong bonds with thiol-containing ligands, which makes it possible to attach targeting ligands, polymers, peptides, oligonucleotides, and drugs in a controlled way. This chemistry is one reason AuNPs are frequently used as programmable nanocarriers in drug delivery research.

A second characteristic is their plasmonic optical behavior. Gold nanoparticles absorb and scatter light strongly because of localized surface plasmon resonance. This property is especially valuable in photothermal therapy and in light-triggered therapeutic strategies. Shape and size directly influence this optical response, which means that AuNPs can be engineered for different biomedical purposes.

AuNPs are also considered useful because they are relatively stable colloidal systems and are often described as biocompatible in many formulations. In addition, they can support multifunctional designs, combining drug delivery, imaging, and therapy in a single platform. This makes them attractive in oncology and theranostics.

Intrinsic anticancer effects: what is known

Several studies have reported that AuNPs may exert direct anticancer effects through oxidative stress, mitochondrial dysfunction, apoptosis, cell-cycle arrest, and modulation of survival signaling pathways. In some systems, AuNPs can also enhance photothermal therapy or radiosensitization, which adds another anticancer mechanism.

At the same time, these effects are not universal. They depend strongly on the physicochemical properties of the nanoparticle, including size, shape, surface coating, concentration, and the biological model used. For example, studies comparing different gold nanostructures have shown that nanostars, rods, cages, and spheres can differ in heat generation, cellular uptake, and apoptotic response. This means that the observed biological effect often reflects how the nanoparticle is engineered rather than the gold core alone.

How to isolate a true gold-specific effect

If the goal is to determine whether gold itself contributes to anticancer activity, the most rigorous approach would be to compare nanoparticles that are identical in size, shape, concentration, and coating, differing only in core composition. Such comparisons would help separate a true gold effect from broader nanoscale or surface-driven effects. Here are some studies that compared nanoparticles with matched physicochemical parameters, varying only core composition:

  • Same Polymer Coating, Varied Core: Bryce et al. (2013) - Iron oxide, gold, and silica cores, all 10–15 nm, coated with the same amphiphilic block copolymer (95% MPEG / 5% NH₂), tested identically in 3D tumor spheroids. Conclusion: core composition played no role — the polymer end-group alone governed drug co-delivery efficacy.
  • Gold vs. Silver: Matched Size, Shape, and Coating: Liu et al. (2016) - AuNPs vs. AgNPs, both ~15 nm spheres, both citrate-capped, identical zeta potential (~−35 mV), tested at matched mass and molar concentrations in U251 glioma cells and an orthotopic mouse model under 6 MV X-ray irradiation. Conclusion: AgNPs outperformed AuNPs as radiosensitizers.
  • Bimetallic Gradients: Isolating the Gold Fraction: 

    o   Chernousova et al. (2015) - Nine Ag:Au molar ratios (10:90 to 90:10), all ~6–8 nm, all PVP-coated, tested on HeLa cells and hMSCs. Conclusion: cytotoxicity was non-proportional to silver content — 80% Ag/20% Au was most toxic, with gold modulating (not simply passivating) silver bioactivity in a non-linear way. 

    o   Shmarakov et al. (2017) - AgAu NPs in three Ag:Au ratios (1:1, 1:3, 3:1) plus two topologies (Au_core/Ag_shell vs Ag_core/Au_shell) tested in a Lewis lung carcinoma mouse model. Conclusion: antitumor efficacy depended on the topology of gold at the surface - Ag_core/Au_shell particles were most effective, pointing to the gold surface chemistry rather than bulk gold content as the key variable.

  • Iron Core vs. Gold Shell: Component Dissection: Wu (2013) et al. - Fe@Au core-shell NPs compared to Fe-only NPs (same synthesis minus the gold step) across four cancer cell lines. Conclusion: the gold shell was not passive, but it was an active contributor to cytotoxicity in iron-resistant cells, with both the Fe core and Au shell being necessary for full anticancer activity.

We were not able to identify any study that simultaneously controlled for all four parameters (size, shape, concentration, and coating) while varying only gold vs. a non-gold inert core across a comprehensive biological endpoint panel. The Bryce et al. (2013) study comes closest but focuses on drug co-delivery rather than intrinsic gold bioactivity. Thus, isolating a true gold-specific effect remains an important direction for future research.

Why the gold core still matters

The gold core is important because it provides a very useful set of physical properties. It allows robust ligand attachment, strong optical response, and shape-dependent tuning of biological behavior. Gold also contributes to the performance of dual-function platforms in which the nanoparticle serves both as a carrier and as a therapeutic component, for example in photothermal or combined chemo-photothermal strategies.

A useful way to think about it is this: gold does not make every nanoparticle biologically superior, but it does offer a distinctive engineering platform. That platform is especially valuable when precise surface control and optical responsiveness are required.

References:

1. Georgeous, J., AlSawaftah, N., Abuwatfa, W. H., & Husseini, G. A. (2024). Review of Gold Nanoparticles: Synthesis, Properties, Shapes, Cellular Uptake, Targeting, Release Mechanisms and Applications in Drug Delivery and Therapy. Pharmaceutics, 16(10), 1332. https://doi.org/10.3390/pharmaceutics16101332

2. Zhang, J., Mou, L., & Jiang, X. (2020). Surface chemistry of gold nanoparticles for health-related applications. Chem. Sci., 2020,11, 923-936.  https://doi.org/10.1039/c9sc06497d

3. Nguyen, T. T. A., Dutour, R., Conrard, L., Vermeersch, M., Mirgaux, M., Perez-Morga, D., Baeyens, N., Bruylants, G., & Demeestere, I. (2025). Effect of Surface Modification of Gold Nanoparticles Loaded with Small Nucleic Acid Sequences on Cytotoxicity and Uptake: A Comparative Study In Vitro. ACS applied bio materials, 8(4), 3040–3051. https://doi.org/10.1021/acsabm.4c01861

4. Amina SJ, Guo B. (2020) A Review on the Synthesis and Functionalization of Gold Nanoparticles as a Drug Delivery Vehicle. Int J Nanomedicine15:9823-9857. https://doi.org/10.2147/IJN.S279094

5. Badir, A., Refki, S., & Sekkat, Z. (2025). Utilizing gold nanoparticles in plasmonic photothermal therapy for cancer treatment. Heliyon, 11, e42738. https://doi.org/10.1016/j.heliyon.2025.e42738

6. Rosario-Berríos, D. N., Pang, A., Liu, L. P., Maidment, P. S. N., Kim, J., Yoon, S., Nieves, L. M., Mossburg, K. J., Adezio, A., Noël, P. B., Lennon, E. M., & Cormode, D. P. (2025). The effect of the size of gold nanoparticle contrast agents on CT imaging of the gastrointestinal tract and inflammatory bowel disease. Bioconjugate Chemistry, 36(2), 233–244. https://doi.org/10.1021/acs.bioconjchem.4c00507

7. Yang, Y., Zheng, X., Chen, L., Gong, X., Yang, H., Duan, X., & Zhu, Y. (2022). Multifunctional gold nanoparticles in cancer diagnosis and treatment. International Journal of Nanomedicine, 17, 2041–2067. https://doi.org/10.2147/IJN.S355142

8. Bloise, N., Strada, S., Dacarro, G., & Visai, L. (2022). Gold Nanoparticles Contact with Cancer Cell: A Brief Update. International Journal of Molecular Sciences, 23(14), 7683. https://doi.org/10.3390/ijms231476839. 

9. Loscertales, E., Lopez-Mendez, R., Mateo, J., Fraile, L. M., Udias, J. M., Espinosa, A., & Espana, S. (2025). Impact of gold nanoparticle size and coating on radiosensitization and generation of reactive oxygen species in cancer therapy. Nanoscale Advances. https://doi.org/10.1039/d4na00773e

10. Yeh, C.-S., Manoharan, D., Sheu, H., Wang, H.-C., Chen, J.-S., Chang, L.-C., Chang, M.-C., Chang, P.-Y., Li, W.-P., Wang, W.-J., Su, W.-P., Chiu, W.-T., Liu, Y.-L., Liu, Y.-F., & Chen, Y.-C. (2025). Redox disruption using electroactive liposome coated gold nanoparticles for cancer therapy. Nature Communications, 16, 3421. https://doi.org/10.1038/s41467-025-58636-2

11. David, S., Patel, D., Cardona, S., Kirby, N., & Mayer, K. (2022). Cellular uptake and cytotoxicity of PEGylated gold nanoparticles in C33A cervical cancer cells. Nano Express. https://doi.org/10.1088/2632-959X/ac7738

12. Bidian, C., Filip, G. A., David, L., Moldovan, B., Olteanu, D., Clichici, S., Olănescu-Vaida-Voevod, M.-C., Leostean, C., Macavei, S., Muntean, D. M., Cenariu, M., Albu, A., & Baldea, I. (2023). Green Synthesized Gold and Silver Nanoparticles Increased Oxidative Stress and Induced Cell Death in Colorectal Adenocarcinoma Cells. Nanomaterials, 13(7), 1251. https://doi.org/10.3390/nano13071251

13. Lin, J., Wang, S., Huang, P., Wang, Z., Chen, S., Niu, G., He, J., Cui, D., Lu, G., Chen, X., & Nie, Z. (2013). Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano, 7(6), 5320-5329. https://doi.org/10.1021/nn4011686

14. Kus-Liśkiewicz, M., Fickers, P., & Ben Tahar, I. (2021). Biocompatibility and Cytotoxicity of Gold Nanoparticles: Recent Advances in Methodologies and Regulations. International Journal of Molecular Sciences, 22(20), 10952. https://doi.org/10.3390/ijms222010952

15. Bryce, N. S., Pham, B. T. T., Fong, N. W. S., Jain, N., Pan, E. H., Whan, R. M., Hambley, T. W., & Hawkett, B. S. (2013). The composition and end-group functionality of sterically stabilized nanoparticles enhances the effectiveness of co-administered cytotoxins. Biomaterials Science, 1(12), 1264–1272. https://doi.org/10.1039/C3BM60120J

16. Liu, P., Jin, H., Guo, Z., Ma, J., Zhao, J., Li, D., Wu, H., & Gu, N. (2016). Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma. International Journal of Nanomedicine, 11, 5003–5014. https://doi.org/10.2147/IJN.S115473

17. Chernousova, S., Ristig, S., Meyer-Zaika, W., & Epple, M. (2015). Synthesis, characterization and in vitro effects of 7 nm alloyed silver–gold nanoparticles. Beilstein Journal of Nanotechnology, 6, 1212–1220. https://doi.org/10.3762/bjnano.6.124

18. Shmarakov, I., Mukha, I., Vityuk, N., Borschovetska, V., Zhyshchynska, N., Grodzyuk, G., & Eremenko, A. (2017). Antitumor activity of alloy and core-shell-type bimetallic AgAu nanoparticles. Nanoscale Research Letters, 12, 238. https://doi.org/10.1186/s11671-017-2112-y

19. Wu, Y., Wu, P.-C., Yang, L.-X., Ratinac, K. R., Thordarson, P., Jahn, K. A., Chen, D.-H., Shieh, D.-B., & Braet, F. (2013). The anticancer properties of iron core–gold shell nanoparticles in colorectal cancer cells. International Journal of Nanomedicine, 8, 3321–3331. https://doi.org/10.2147/IJN.S47742

Back to blog