Advances in lung-on-a-chip platforms for nanotherapeutic evaluation and screening

Improvements in drug solubility, targeting, and pharmacokinetics achieved through nanomedicine have driven the advancement of nanoparticle-based therapeutics. These formulations, administered either systemically or via pulmonary delivery, are promising treatments for a range of respiratory diseases. A significant barrier to the development and clinical translation of lung-targeted nano-based drug delivery systems is the lack of physiologically relevant preclinical in vitro models that enable the screening of these systems with a high correlation to in vivo tests. Microfluidic lung-on-a-chip devices offer a solution by creating a three-dimensional microenvironment that recapitulates key features of in vivo lung physiology and organ-level functions. Incorporation of mechanical cues and multi-cell type cultures within these devices influences nanoparticle transport dynamics, cellular uptake, and therapeutic efficacy. The application of lung-on-a-chip devices as biomimetic tools for disease modelling has been widely reviewed. This review focuses on recent advances in employing these microengineered models to screen and evaluate the effectiveness of pulmonary nanotherapeutics. It provides insights into the interactions between nanoparticle physicochemical properties such as size, shape, and surface charge, and key microenvironmental factors of lung-on-a-chip devices including shear stress and cyclic mechanical stretch. Alongside this is a discussion of considerations, including host device design, scaffold material, and cell source, for the successful development of lung-on-a-chip models as screening platforms. The review concludes by highlighting challenges and emphasizing the need for platforms with enhanced screening throughput and greater biological fidelity.