Enteric-coated magnesium-propelled polymersome nanomotors for pH-triggered intestinal activation and mucosal IgA induction

Oral vaccines must withstand gastric acid and mucus, reach microfold cells, and trigger durable mucosal IgA, but most carriers cannot simultaneously provide enteric protection, on-demand intestinal activation, and predictable biodegradation. We present magnesium-propelled polymersome (PSome) nanomotors (ActiPSomes) that conserve chemical fuel in the stomach via an enteric overcoat and activate in the intestine to enhance transport and antigen encounter. After coating, the hydrodynamic diameter increased from 141.33 ± 3.62 nm to 188.63 ± 2.03 nm, confirming formation of a protective layer. Nanoparticle-tracking analysis showed negligible directional motion under gastric conditions (pH 2.0) but pronounced propulsion at intestinal pH (pH 8.0); the size mobility relationship followed MSD theory with R² ≈ 0.96. In vitro, ActiPSomes increased macrophage uptake of Nile-red-labeled antigen ∼2.8-fold versus particles without magnesium and maintained a ∼2.1-fold advantage after sequential exposure to simulated gastric and intestinal environments. In vivo, oral dosing elicited significantly higher PEDV-specific IgA titers in feces and intestines at days 7 and 14 compared with controls (p < 0.05-0.001), with no adverse clinical signs or weight loss over 14 days. Mechanistically, intestinal pH dissolves the enteric layer to expose intravesicular Mg, generating hydrogen that drives active diffusion while PLA hydrolysis supports intestinal biodegradation. These data establish a generalizable nanoplatform for enteric-protected, fuel-efficient oral vaccination against mucosal pathogens. In this study, we developed magnesium-propelled PSome nanomotors, termed ActiPSomes, that integrate enteric protection, pH-triggered propulsion, and intestinal biodegradation to enhance oral antigen delivery and mucosal immunity.