Nanomaterials: a brief review and regulatory considerations


Nanomaterials are defined as a natural, incidental or manufactured materials consisting of solid particles that are present, either on their own or as identifiable constituent particles in aggregates or agglomerates, and where 50 % or more of these particles in the number-based size distribution fulfil at least one of the following conditions[1],[2]:

  • one or more external dimensions of the particle are in the size range 1 nm to 100 nm;
  • the particle has an elongated shape, such as a rod, fiber, or tube, where two external dimensions are smaller than 1 nm and the other dimension is larger than 100 nm;
  • the particle has a plate-like shape, where one external dimension is smaller than 1 nm and the other dimensions are larger than 100 nm.

In the determination of the particle number-based size distribution, particles with at least two orthogonal external dimensions larger than 100 μm do not need to be considered, as well as materials with a specific surface area by volume of <6 m2/cm3[3].

Over the past decade, the applications of nanomaterials have undergone an exponential growth across many different fields, showing promising properties in many of them. This growth is due to their flexibility: indeed, nanomaterials are characterized by an array of peculiar chemico-physical properties, allowing for their functionalization and adaptation to many different applications. Notably, these unique physical traits depend on their size and shape, while for bulk materials physical properties are independent of size[4]. For instance graphene, one of the most famous nanomaterials, is highly resistant with an intrinsic strength of 42 N/m[5], has an optic transparency of 97.7%[6], has a large surface area (2630 m2/g)[7] and a good electrical conductivity[8], to mention a handful.

Amongst nanoparticulate materials possible uses, one of the most interesting and promising is as nanocarriers, especially for drug- and gene- delivery technology, since nanoparticles’ dimensions are comparable to those of biomolecules, such as DNA (diameter of ~2 nm), cell membranes (∼6–10 nm) and proteins (1–20 nm)[9]. In fact, numerous studies have documented the effective delivery of both hydrophilic and hydrophobic drugs, proteins, biological macromolecules, and even vaccines utilizing nanoparticles as carriers[10]. Newer tools for gene therapy include directly acting nucleic acid sequences such as microRNA, RNAi via short hairpin RNAs (shRNA), molecular scissor and gene editing approaches such as CRISPR-Cas, Zinc finger nucleases (ZFNs) or TALENs. These may affect repair, addition or deletion of a genetic sequence via gene silencing, exon skipping, gene regulation, gene knockdown and nucleotide changes[11],[12].

Nanomaterials of particular interest for these applications include inorganic nanoparticles, dendrimers, polymers and liposomes, thanks to their good biocompatibility, high drug-load capacity, high stability, enhanced bioavailability, sustained and controlled drug release and the possibility of tracing the drug delivery, just to name a few[13].

Many research groups nowadays are developing drug delivery systems (DDS) based on bionanoparticles, by functionalizing nanomaterials with polymers from natural or synthetic origins. Amongst the most used polymers for these scopes we find silk, albumin, collagen, cellulose, starch and alginates in various forms[14]. The obtained DDS was shown to exhibit higher biodegradability, biocompatibility, low immunogenicity and antibacterial activity[15] with the additional quality of a better protection of carried drugs from degradation[16]. Diverse bionanoparticles are being produced using different technological methods such as electrospraying[17], spray-drying[18], supercritical fluid extraction[19], and microemulsion[20], each producing bionanoparticles having different characteristics.

The safety evaluation and risk assessment of nanomaterials requires particular attention. Even when composed of the same chemical substance, nanomaterials can manifest distinct toxicological risk profiles influenced by variables like size, surface chemistry, physicochemical properties, and the intended application. From a regulatory standpoint, EN ISO 10993-22 provides an overview and highlights important considerations in the safety assessment of medical devices consisting of, containing or producing nano-objects. However, no detailed test protocols are outlined or provided, but it identifies several common pitfalls and barriers when testing nanomaterials versus bulk materials or small molecule chemical species. Considering the potential presence of nanomaterials, a specific risk assessment following ISO 10993-1 and -22 must be conducted for substances falling within the nanomaterial size range.

Considering the extent of nanomaterials applications in the biomedical field and the level of innovation they could produce, such materials continue to show criticalities. As of today, the full extent of their harmful effects and long-term effects on organisms remains uncertain, both due to their unique characteristics, which differ significantly from those of bulk materials[21], and due to the scarcity of proper toxicological studies, considering the majority of these applications are still in the embryonal phase.

At ToxHub we have worked with several projects involving naonmaterials: contact us for any of your nanomaterial toxicological needs!

Article issued by Chiara Gazerro 


[1] Commission Recommendation of 10 June 2022 on the definition of nanomaterial (Text with EEA relevance) 2022/C 229/01. Published: 2022-06-10

[2] ISO 10993-22:2017. Biological evaluation of medical devices – Guidance on nanomaterials


[4] Saleh, T. A. (2020). Nanomaterials: Classification, properties, and environmental toxicities. Environmental Technology & Innovation, 20, 101067.

[5] Lee, C., Wei, X., Kysar, J.W., Hone, J., 2008. Measurement of the Elastic Properties and Intrinsic Strength of Monolayer Graphene. Science 321, 385–388.

[6] Papageorgiou, D.G., Kinloch, I.A., Young, R.J., 2017. Mechanical properties of graphene and graphene-based nanocomposites. Prog. Mater. Sci. 90, 75–127.

[7] Zhu, Y., Murali, S., Cai, W., Li, X., Suk, J. W., Potts, J. R., & Ruoff, R. S. (2010). Graphene and graphene oxide: synthesis, properties, and applications. Advanced materials, 22(35), 3906-3924.

[8] Potts, J. R., Dreyer, D. R., Bielawski, C. W., & Ruoff, R. S. (2011). Graphene-based polymer nanocomposites. Polymer, 52(1), 5-25.

[9] Riehemann, K.; Schneider, S.W.; Luger, T.A.; Godin, B.; Ferrari, M.; Fuchs, H. Nanomedicine—Challenge and perspectives. Angew. Chem. Int. Engl. 2009, 48, 872–897.

[10] Din, F.U.; Aman, W.; Ullah, I.; Qureshi, O.S.; Mustapha, O.; Shafique, S.; Zeb, A. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int. J. Nanomed. 2017, 12, 7291–7309.

[11] EMA 2014: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CAT/80183/2014

[12] Wirth T, Parker N, Ylä-Herttuala S. History of gene therapy. Gene. 2013 Aug 10;525(2):162-9. doi:10.1016/j.gene.2013.03.137. Epub 2013 Apr 23. PMID: 23618815.

[13] Shuai Zha, Haitao Liu, Hengde Li, Haolan Li, Ka-Leung Wong, and Angelo Homayoun All ACS Nano 2024 18 (3), 1820-1845 DOI: 10.1021/acsnano.3c10674.

[14] Jacob, J., Haponiuk, J. T., Thomas, S., & Gopi, S. (2018). Biopolymer based nanomaterials in drug delivery systems: A review. Materials Today Chemistry, 9, 43–55. doi:10.1016/j.mtchem.2018.05.002

[15] Gopi, S., Amalraj, A., & Thomas, S. (2016). Effective drug delivery system of biopolymers based on nanomaterials and hydrogels-a review. Drug Des, 5(129), 2169-0138.

[16] Yang, Y. Y., Wang, Y., Powell, R., & Chan, P. (2006). Polymeric core-shell nanoparticles for therapeutics. Clinical and Experimental Pharmacology and Physiology, 33(5), 557-562.

[17] Bakhsheshi-Rad, H. R., Hadisi, Z., Hamzah, E., Ismail, A. F., Aziz, M., & Kashefian, M. (2017). Drug delivery and cytocompatibility of ciprofloxacin loaded gelatin nanofibers-coated Mg alloy. Materials Letters, 207, 179-182.

[18] Jiang, W. Z., Cai, Y., & Li, H. Y. (2017). Chitosan-based spray-dried mucoadhesive microspheres for sustained oromucosal drug delivery. Powder technology, 312, 124-132.

[19] Salerno, A., Verdolotti, L., Raucci, M. G., Saurina, J., Domingo, C., Lamanna, R., … & Lavorgna, M. (2018). Hybrid gelatin-based porous materials with a tunable multiscale morphology for tissue engineering and drug delivery. European Polymer Journal, 99, 230-239.

[20] Bonilla, P., Arias, E. M., Solans, C., & García-Celma, M. J. (2018). Influence of crosslinked alginate on drug release from highly concentrated emulsions. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 536, 148-155.

[21] Sachin P. Borikar, Shirish P. Jain, Deepali N. Tapre, Debarshi Kar Mahapatra, Asavari V. Mahajan, Dipak S. Sonawane, Prakash N. Kendre, Chapter 25 – Neurotoxicity with the use of nanomaterials, Editor(s): Bhupendra Gopalbhai Prajapati, Dinesh Kumar Chellappan, Prakash N. Kendre, Alzheimer’s Disease and Advanced Drug Delivery Strategies, Academic Press, 2024, Pages 421-438, ISBN 9780443132056,

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