(Re)evolution in nanoparticles-loaded microneedle delivery systems: are we getting closer to a clinical translation?

The deposition of drug-loaded nanoparticles within the skin structure has been a challenge due to the inexorable skin barrier function. Unless specific nanoparticles like liposomes and lipid-based related vesicles, most nanoparticles cannot penetrate the epidermal layers by themselves. This is the reason why microneedle-based systems are nowadays the most straightforward systems in skin research. They can greatly bypass the and deposit the supramolecular cargo entities in the dermal layers, which can perform specific features such as drug-controlled release, specific targeting or stimuli-responsive behaviors. At this point, after more than 20 years of research using this nanoparticle-microneedle combination and all the positive results, the clinical experience is still so limited. Therefore, how is it possible that the everlasting promise of the clinical translation of these systems has not reached a real clinical practice? In this piece of work, based on authors' review, a series of limiting factors as the regulatory framework and guidelines are identified and discussed, while it is highlighted that revolutionary advances in the biomedical field such as 3D-printing technology and microfluidics will contribute to accelerate the clinical translation of nanoparticle-microneedle-based devices and make possible their use and entrance to the biomedical market.