Lessons from the history of inorganic nanoparticles for inhalable diagnostics and therapeutics

The respiratory tract is one of the most accessible ones to exogenous nanoparticles, yet drug delivery by their means to it is made extraordinarily challenging because of the plexus of aerodynamic, hemodynamic and biomolecular factors at cellular and extracellular levels that synergistically define the safety and efficacy of this process. Here, the use of inorganic nanoparticles (INPs) for inhalable diagnostics and therapies of the lung is viewed through the prism of the history of studies on the interaction of INPs with the lower respiratory tract. The most conceptually and methodologically innovative and illuminative studies are referred to in the chronological order, as they were reported in the literature, and the trends in the progress of understanding this interaction of immense therapeutic and toxicological significance are being deduced from it. The most outstanding actual trends delineated include the diminishment of toxicity via surface functionalization, cell targeting, tagging and tracking via controlled binding and uptake, hybrid INP treatments, magnetic guidance, combined drug and gene delivery, use as adjuvants in inhalable vaccines, and other. Many of the understudied research directions, which have been accomplished by the nanostructured organic polymers in the pulmonary niche, are discussed. The progress in the use of INPs as inhalable diagnostics or therapeutics has been hampered by their well-recognized inflammatory potential and toxicity in the respiratory tract. However, the annual numbers of methodologically innovative studies have been on the rise throughout the past two decades, suggesting that this is a prolific direction of research, its comparatively poor commercial takings notwithstanding. Still, the lack of consensus on the effects of many INP compositions at low but therapeutically effective doses, the plethora of contradictory reports on ostensibly identical chemical compositions and NP properties, and the many cases of antagonism in combinatorial NP treatments imply that the rational design of inhalable medical devices based on INPs must rely on qualitative principles for the most part and embrace a partially stochastic approach as well. At the same time, the fact that the most studied INPs for pulmonary applications have been those with some of the thickest records of pulmonary toxicity, e.g., carbon, silver, gold, silica and iron oxide, is a silent call for the expansion of the search for new inorganic compositions for use in inhalable therapies to new territories.