Macrophage-derived exosome as bioengineered nanotherapeutics for silica-induced reproductive dysregulation.

Engineered nanomaterials pose emerging challenges for human health, particularly reproductive toxicity stemming from occupational silica nanoparticles (SiNPs) exposure. This study demonstrates the development and application of macrophage-derived exosome (M-Exo) as bioengineered nanotherapeutics for treating SiNPs-induced male reproductive dysfunction. We characterized M-Exo using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS), confirming M-Exo with cup-shaped morphology, mean hydrodynamic diameter of 163.2 ± 2.4 nm, excellent monodispersity (PDI = 0.13), and concentration of 1.93 × 1011 particles/mL. In vivo biodistribution studies using fluorescently-labeled M-Exo revealed targeted testicular accumulation with peak retention at 8 h post-intratracheal administration. SiNPs exposure (100 mg/mL) disrupted spermatogenesis through Wnt signaling dysregulation, causing G2/M cell cycle arrest and oxidative damage. M-Exo treatment functioned as a precision nanomedicine, restoring sperm motility from 70.8 ± 1.2​​​​​​​% to 76.2 ± 7.3%, reducing abnormality rates from 16.4 ± 1.1% to 11.6 ± 1.1%, and normalizing testicular architecture. Mechanistically, M-Exo normalized aberrant Wnt pathway activation while enhancing cellular antioxidant capacity. In conclusion, we demonstrate that M-Exo can repair SiNPs-induced reproductive damage potentially through modulation of the Wnt signaling pathway, which establishes M-Exo as an innovative platform for targeted delivery of regenerative signals.