Spore-inspired surface engineering enhances macrophage phagocytosis for inhalation therapy of acute lung injury

Acute lung injury (ALI) is a life-threatening pulmonary disease characterized by oxidative stress and excessive inflammation. Although quercetin (QU) has strong antioxidant and anti-inflammatory activity, the effect of inhalation administration is still limited due to its insufficient deposition in the alveoli and low uptake efficiency by alveolar macrophages. To overcome these obstacles, we have developed a biomimetic inhalable platform quercetin-loaded carbonized Aspergillus oryzae spore (QU-cASP) inspired by the microstructure of fungal spores. The carbonized Aspergillus oryzae spore (cASP) retained the native microstructure of the spores while forming a carbonaceous skeleton, thereby enhancing drug-loading capacity and structural stability. Meanwhile, its rough surface significantly enhanced the surface-assisted phagocytic effect of macrophages, thus promoting the intracellular delivery of QU. In addition, the mass median aerodynamic diameter (MMAD) of QU-cASP fell within the optimal inhalable range, enabling efficient pulmonary deposition. In the ALI models, inhalation of QU-cASP could effectively relieve oxidative stress, reduce pro-inflammatory cytokines, and promote macrophage polarization toward the anti-inflammatory M2 phenotype. Transcriptomic analysis and Western blot analysis showed that the inflammatory-related signaling pathway was inhibited. In summary, this study establishes a spore-inspired surface-assisted phagocytosis strategy, which bridges the gap between aerodynamic delivery and cell delivery. Meanwhile, QU-cASP holds a remarkable translational prospect for the precision treatment of ALI and related lung inflammatory diseases.