Ultrasound-activated directional and controllable nitric oxide therapy for vascular calcification repair through the modulation of eNOS/iNOS homeostasis.

Vascular calcification (VC) is a critical pathological hallmark of cardiovascular diseases but current therapeutic options remain inadequate. Nitric oxide (NO) homeostasis plays a vital role in endothelial function and phenotypic transformation of vascular smooth muscle cells (VSMCs), two key pathological processes in VC. In this study, Fe₃O₄@PDA@BNN6 (FPB) nanoparticles were prepared for directional and controllable NO therapy. Magnetic field enriched the nanoparticles to the site of VC and ultrasound triggered the controllable release of NO to regulate the homeostasis of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), further activated sGC-cGMP-PKG signaling pathway. Both in the rat and in vitro VC models, the innovative therapy inhibited osteogenic like transformation of VSMCs, alleviated endothelial inflammatory response, regulated eNOS/iNOS homeostasis, and effectively improved VC. By ensuring optimal NO bioavailability for vascular homeostasis, this magneto-ultrasonically controlled strategy overcomes limitations of conventional NO-based therapies and paves the way for precision NO-mediated interventions in cardiovascular diseases. STATEMENT OF SIGNIFICANCE: Engineering innovation: Dual-modality nanoparticle system for precision NO delivery: Magnetic guidance directs the FPB to calcified lesions, reducing systemic off-target effects. Ultrasound-triggered release of NO to ensure on-demand delivery at VC sites. Mechanistic innovation: Restoring eNOS/iNOS homeostasis as a therapeutic axis: Directional and controllable NO therapy uniquely modulates eNOS/iNOS homeostasis, further activating the sGC-cGMP-PKG signaling pathway.