Morphology controlled nanomaterials to navigate mucosal barriers

Mucus layer coats and protects nearly all entry points into the body that are not coated by skin. Mucosal routes are preferred sites for drug administration in comparison with invasive parenteral routes. Nevertheless, the design of drug carriers able to avoid dilution with biological fluids and rapid mucus clearance still represents an unmet challenge for the scientific community. Nanomaterials (NMs) coated with mucoadhesive polymers have shown their ability to address some aspects of these problems, mainly due to their small size and mucoadhesive surface. However, while NM size and surface properties have been extensively studied, there is a lack of investigations on morphology dependent behaviours of NMs towards mucosal barriers. The strategy proposed in our research group is to consider the morphology of NMs as a relevant parameter to make them rapidly reach mucus avoiding dilution with biological fluids, to accumulate at high concentrations close to the mucosal epithelium and to be internalized by epithelial cells. Understanding whether NM morphology impacts their transport into mucus and mucoadhesive behaviors requires robust technological tools to manufacture NMs with controlled properties. Not only by handling the morphology, but also the size and the surface properties, because these parameters are interconnected. In this context, our research group has recently developed complementary processes to design morphology controlled NMs with simultaneous control of aspect ratio, size and versatile surface modification. We revealed that non-spherical morphology NMs results from different physical and biological behaviours, compared with spherical particles. Indeed, NMs with flat surfaces and sharp edges had faster mobility in biological fluids and higher receptor-dependent cell internalization. They also exhibited faster mucoadhesion than spherical particles. Using real-time in vivo imaging on a rat model, we revealed that flattened NMs had longer residence time in the intestine compared to spherical particles. Finally, we showed that flattened NMs did not exhibit same biological behaviors that spherical ones for the treatment of mucosal infections.

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