The use of synthetic materials and the attention towards environmental hazards and toxicity impose the development of green composites with natural origins. Clay is one of the candidates for this approach. Halloysite is a natural clay mineral, a member of the Kaolin group, with characteristic tubular morphology, usually named halloysite nanotubes (HNTs). The different surface chemistry of halloysite allows the selective modification of both the external surface and the inner lumen by supramolecular or covalent interactions. An interesting aspect of HNTs is related to the possibility of introducing different species that can be released more slowly compared to the pristine compound. Due to their unique hollow morphology and large cavity, HNTs can be employed as an optimal natural nanocarrier. This review discusses the structure, properties, and application of HNTs in the biological field, highlighting their high biocompatibility, and analyse the opportunity to use new HNT hybrids as drug carriers and delivery systems.

The need for safe, therapeutically effective, and patient-compliant drug delivery systems continuously leads researchers to design novel tools and strategies. Clay minerals are widely used in drug products both as excipients and active agents but, in recent years, there has been a growing interest in research aimed at the development of new organic or inorganic nanocomposites. The attention of the scientific community has been drawn by nanoclays, thanks to their natural origin, worldwide abundance, availability, sustainability, and biocompatibility. In this review, we focused our attention on the studies inherent to the pharmaceutical and biomedical applications of halloysite and sepiolite, and their semi-synthetic or synthetic derivatives, as drug delivery systems. After having described the structure of both materials and their biocompatibility, we delineate the use of the nanoclays to enhance the stability, the controlled release, the bioavailability, and the adsorption properties of drugs. Several types of surface functionalization have been discussed, showing that these materials could be used for the development of an innovative therapeutic approach.

Purpose: Halloysite nanotubes (HNTs) are a natural aluminosilicate clay with a chemical formula of Al₂Si₂O₅(OH)₄×nH₂O and a hollow tubular structure. Due to their peculiar structure, HNTs can play an important role as a drug carrier system. Currently, the mechanism by which HNTs are internalized into living cells, and what is the transport pathway, is still unclear. Therefore, this study aimed at establishing the in vitro mechanism by which halloysite nanotubes could be internalized, using phagocytic and non-phagocytic cell lines as models. Methods: The HNT/CURBO hybrid system, where a fluorescent probe (CURBO) is confined in the HNT lumen, has been used as a model to study the transport pathway mechanisms of HNTs. The cytocompatibility of HNT/CURBO on cell lines model was investigated by MTS assay. In order to identify the internalization pathway involved in the cellular uptake, we performed various endocytosis-inhibiting studies, and we used fluorescence microscopy to verify the nanomaterial internalization by cells. We evaluated the haemolytic effect of HNT/CURBO placed in contact with human red blood cells (HRBCs), by reading the absorbance value of the supernatant at 570 nm. Results: The HNT/CURBO is highly biocompatible and does not have an appreciable haemolytic effect. The results of the inhibition tests have shown that the internalization process of nanotubes occurs in an energy-dependent manner in both the investigated cell lines, although they have different characteristics. In particular, in non-phagocytic cells, clathrin-dependent and independent endocytosis are involved. In phagocytic cells, in addition to phagocytosis and clathrin-dependent endocytosis, microtubules also participate in the halloysite cellular trafficking. Upon internalization by cells, HNT/CURBO is localized in the cytoplasmic area, particularly in the perinuclear region. Conclusion: Understanding the cellular transport pathways of HNTs can help in the rational design of novel drug delivery systems and can be of great value for their applications in biotechnology.