A review on micro and nanoengineering in powder-based pulmonary drug delivery

Pulmonary delivery of drugs has emerged as a promising approach for the treatment of both lung and systemic diseases. Compared to other drug delivery routes, inhalation offers numerous advantages including high targeting, fewer side effects, and a huge surface area for drug absorption. However, the deposition of drugs in the lungs can be limited by lung defence mechanisms such as mucociliary and macrophages ' clearance. Among the delivery devices, dry powder inhalers represent the optimal choice due to their stability, ease of use, and absence of propellants. In the last decades, several bottom-up techniques have emerged over traditional milling to produce inhalable powders. Among these techniques, the most employed ones are spray drying, supercritical fluid technology, spray freeze-drying, and thin film freezing. Inhalable dry powders can be constituted by micronized drugs attached to a coarse carrier (e.g., lactose) or drugs embedded into a micro- or nanoparticle. Particulatebased formulations are commonly composed of polymeric micro- and nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, nanocrystals, extracellular vesicles, and inorganic nanoparticles. Moreover, engineered formulations including large porous particles, swellable microparticles, nano-in-microparticles, and effervescent nanoparticles have been developed. Particle engineering has also a crucial role in tuning the physical -chemical properties of both carrier-based and carrier-free inhalable powders. This approach can increase powder flowability, deposition, and targeting by customising particle surface features.