pH-Responsive Nanostructured Calcium Phosphate Microrods as Pulmonary Delivery Platform: Fabrication, Characterization, and Comparative Assessment of Cytotoxic and Transcriptomic Responses in Alveolar Macrophages

Nanostructured, rod-shaped microparticles represent a promising drug-delivery plat-form for pulmonary delivery and targeting of alveolar macrophage by leveraging the aerodynamic advantages of fiber-like geometries. These microrods feature a hierar-chical architecture, designed for potential macromolecular payloads, and silica-based systems have previously been shown to successfully deliver oligonucleotides in vitro. However, current microrod systems mainly rely on nanoparticulate silica-based frameworks with limited biodegradibility and lack targeted disintegration under the acidic conditions encountered in phagolysosomes. Therefore, a nanostructured calcium phosphate framework is proposed as a biodegradable and resorbable alternative with pH-responsive characteristics. This study describes the fabrication of nanostructured, rod-shaped calcium phosphate microparticles and discusses their suitability as a po-tential pulmonary drug-delivery platform. The particles feature a dissolution-driven disintegration in acidic and ion-rich environments relevant to phagolysosomes. In ad-dition, the particles exhibited a favorable acute cytotoxicity profile in the murine alve-olar macrophage cell line MH-S compared with their SiO2-based counterpart. Com-parative RNA-seq analysis of MH-S that are exposed to the particles indicate a mild transcriptomic response, while canonical signatures of classical or alternative macro-phage activation programs were not observed, supporting a generally well-tolerated exposure profile of the carrier. Together, these findings establish key prerequisites for employing calcium phosphate microrods as a biodegradable pulmonary carrier plat-form in subsequent studies incorporating therapeutic cargo.