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

Abstract

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.

Introduction

Respiratory diseases such as asthma, COPD, pulmonary infection, fibrosis, vascular disorders, and lung cancer differ in pathology, but inhaled therapy faces a shared practical problem: only a fraction of the emitted dose reaches and remains at the intended lung region (Oh et al., 2026, He et al., 2025). Local exposure is shaped by device emission, airway geometry, inspiratory flow, regional ventilation, mucus burden, and disease distribution (Clarà et al., 2023). For poorly soluble drugs, this delivery chain is especially unforgiving because deposition does not guarantee dissolution or pharmacological availability.

The lung offers only a small and unevenly distributed dissolution volume. Deposited particles encounter epithelial lining fluid, mucus, surfactant, inflammatory proteins, extracellular DNA, enzymes, immune cells, and, in infection, microbial biofilms (Kageyama et al., 2024, Roth et al., 2025). These components can change wetting, aggregation, diffusion, dissolution, uptake, and clearance. For poorly soluble inhaled drugs, the key question is therefore not only how fast a particle dissolves in bulk medium, but whether enough drug becomes available before mucociliary clearance, macrophage uptake, tissue binding, or systemic absorption removes it (Yue et al., 2022).

Drug nanocrystals and nanosuspensions have attracted considerable interest for inhaled delivery because they combine high drug loading with enhanced dissolution and relatively low excipient burden (Chavda et al., 2025). Their increased surface area can accelerate dissolution in the limited volume of lung lining fluid, while the high drug fraction is advantageous for inhalation products in which device capacity, treatment duration, and patient tolerance constrain the deliverable dose (Chan et al., 2023). Compared with carrier-based nanosystems such as liposomes, polymeric nanoparticles, micelles, or lipid carriers, nanosuspensions are composed predominantly of active pharmaceutical ingredient, which can be beneficial for high-dose local therapy.

However, the pulmonary benefit of nanosizing depends on whether nanocrystals can be delivered, redispersed, and dissolved at the target site. Individual drug nanocrystals are generally not ideal aerosols because they may be exhaled, aggregate during handling, or be difficult to meter and disperse reproducibly. Pulmonary nanosuspensions therefore require integration across two size scales. The nanoscale drug domains govern dissolution, mucus interaction, macrophage uptake, and cellular availability, whereas the microscale aerosol or droplet properties govern device emission and regional lung deposition. Liquid nanosuspensions may be delivered by nebulization, while dry powder systems often rely on nano-in-micro architectures in which nanocrystals are embedded in respirable microparticles that aerosolize efficiently and subsequently redisperse or dissolve after deposition (Morawska, 2021). In this context, a high fine particle fraction is necessary but not sufficient; post-deposition redispersibility and lung-relevant dissolution are equally important.

Work on pulmonary nanosuspensions has gradually shifted from simple particle-size reduction toward full inhaled-product design. Wet media milling, high-pressure homogenization, microfluidization, antisolvent precipitation, spray drying, freeze drying, and spray freeze drying have all been used to prepare liquid nanosuspensions or nano-in-micro powders (Malamatari et al., 2020). More recent studies also use surface modification to address mucus mobility or macrophage interaction, especially in mucus-rich infection and tuberculosis-related settings (Yu et al., 2016, Chae et al., 2021). Responsive designs are being explored, but their value depends on whether the added complexity improves delivery, exposure, or safety in a measurable way (Ahmad et al., 2026).

Evaluation methods have also progressed beyond conventional particle-size measurement and cascade impaction. These tests remain essential, but they cannot fully predict what happens after particles deposit on diseased airway or alveolar surfaces (Roberts, 2025). Human-relevant and computational tools, including air-liquid interface cultures, mucus and sputum models, biofilm systems, macrophage infection models, patient-derived organoids, lung-on-a-chip platforms, and patient-specific deposition simulations, can help link formulation attributes with redispersion, dissolution, mucus transport, cellular uptake, tissue penetration, toxicity, and interpatient variability. These models are most valuable when selected to answer formulation-specific and disease-specific translational questions.

Previous reviews have summarized important aspects of pulmonary nanocrystals, inhalable nanoparticle-based dry powders, spray-dried nanomedicine powders, pulmonary nanomedicines, inhaled anti-infective nanomedicines, and nanosuspension technologies (Yue et al., 2022, Chan et al., 2023, Rossier et al., 2024, Patil et al., 2025, Ahmed et al., 2025). These reviews have established the importance of particle-size reduction, stabilizer selection, aerosol performance, dry powder engineering, and pulmonary barrier interactions. However, most discussions still treat nanocrystal preparation, aerosolization, biological barriers, and translational evaluation as separate topics. The present review takes a different organizing principle: it asks how these variables should be combined for a given disease barrier and device format. To make this distinction explicit, Table 1 compares the scope of representative previous reviews with the focus of the present article.

Building on this comparison, we examine pulmonary nanosuspensions as inhaled products whose performance is shaped by disease barriers, device behavior, and post-deposition fate. The review connects nanocrystal properties, aerodynamic behavior, matrix design, redispersibility, dissolution, biological barriers, device performance, and translational models, with emphasis on how these variables change across disease settings.

Continue reading here

Yingying Ma, Guohui Zou, Yancai Wang, Pulmonary nanosuspensions for inhaled drug delivery: disease-matched formulation design, biological barriers, and translational evaluation, International Journal of Pharmaceutics, Volume 702, 2026, 127205, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127205.

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