Effects and mechanism of carrier-free self-assembled nanoparticles of natural products in attenuating pulmonary edema.

BACKGROUND

Pulmonary edema, a life-threatening condition in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), is driven by dysregulated inflammation, barrier disruption, and alveolar fluid accumulation. Effective therapies that simultaneously target these multiple pathological processes with high lung specificity are urgently needed.

RESULTS

We engineered carrier-free, self-assembled nanoparticles from the natural products magnolol (Mag) and atractylenolide I (ATI) at an optimal 4:1 molar ratio. The Mag-ATI nanoparticles (MA NPs) exhibited an average hydrodynamic diameter of approximately 220.2 nm, excellent colloidal stability, and a pH-responsive release profile favorable for the acidic pulmonary microenvironment. The drug loading was 81.7 ± 0.356% for Mag and 18.2 ± 0.129% for ATI, encapsulation efficiency exceeded 97% for both. In a murine lipopolysaccharide (LPS)-induced ALI model, MA NPs potently ameliorated pulmonary edema, outperforming individual drugs or their physical mixture. Biodistribution studies confirmed the MA NPs' efficient lung accumulation, with a fluorescence intensity 3.6-5.9 times higher than in other organs, and specific targeting to alveolar epithelial cells. Mechanistically, Mag inhibited TRPV4-mediated Ca2+ influx, thereby suppressing the downstream cAMP/AQP5 axis to limit water permeability and restore alveolar fluid balance. Mag and ATI attenuated inflammatory signaling via the protein kinase B (AKT)/nuclear factor kappa B (NF‑κB) pathway. Furthermore, Mag and ATI preserved epithelial barrier integrity by stabilizing tight junction proteins. These multi-modal mechanisms were systematically validated both in vitro and in vivo. Importantly, MA NPs demonstrated a favorable safety profile with no significant systemic toxicity.

CONCLUSION

This study presents a novel, carrier-free nanotherapeutic platform that integrates the efficacy-enhancing rationale of traditional herbal medicine with advanced nanoassembly. By enabling coordinated modulation of inflammation, barrier function, and fluid homeostasis, MA NPs offer a potent, targeted, and translational strategy for the treatment of ALI/ARDS.