Pulmonary nanosuspensions for inhaled drug delivery: disease-matched formulation design, biological barriers, and...

Pulmonary delivery of poorly water-soluble drugs is constrained by the limited volume of epithelial lining fluid, heterogeneous aerosol deposition, mucociliary clearance, macrophage uptake, mucus obstruction, and disease-dependent alterations in the lung microenvironment. Drug nanocrystals and nanosuspensions offer high drug loading and enhanced dissolution with relatively low excipient burden, but successful inhaled products require more than particle-size reduction alone. This review discusses pulmonary nanosuspensions within a disease-matched, device-integrated, and model-informed design framework. We summarize the physicochemical and biological principles governing aerosol deposition, wetting, redispersion, dissolution, and clearance, and review fabrication strategies for nebulized nanosuspensions and nano-in-micro dry powders. Key formulation attributes, including nanocrystal size, solid-state form, aerodynamic performance, redispersibility, dissolution behavior, moisture sensitivity, stability, and device compatibility, are analyzed in relation to inhaled product performance. We further examine how human-relevant and computational models can guide formulation decisions by assessing mucus transport, epithelial response, macrophage interaction, biofilm penetration, tissue distribution, and patient-specific deposition. Across indications, the value of pulmonary nanosuspensions lies in converting faster nanoscale dissolution into usable local or systemic exposure after aerosolization, deposition, and clearance. Early development needs to address redispersibility, excipient burden, long-term pulmonary safety, and repeated-dose tolerability together with conventional aerosol metrics.