Chemical Science | A natural ultrasound-responsive NO booster FPG provides a novel strategy for atherosclerosis treatment

This study develops a natural ultrasound-responsive nitric oxide (NO) booster FPG capable of targeted NO release, effectively alleviating oxidative stress, suppressing inflammatory responses, and promoting vascular regeneration. The system demonstrates excellent biocompatibility and safety, offering an innovative strategy for treating endothelial dysfunction in atherosclerosis.

 

Literature Overview
This article titled 'A natural ultrasound-triggered nitric oxide booster for endothelial dysfunction therapy', published in the journal Chemical Science, reviews molecular mechanisms and therapeutic strategies for endothelial dysfunction in atherosclerosis (AS). The research focuses on developing a natural, safe, and targeted NO delivery system to overcome toxicity issues associated with existing drugs like statins during long-term use.

Background Knowledge
Atherosclerosis is a chronic inflammatory disease where early vascular endothelial dysfunction manifests as reduced NO bioavailability, elevated ROS levels, and increased inflammatory factor release. Current strategies such as NO-releasing stents and 3D-printed grafts face challenges including poor targeting and uncontrolled release. Developing an extrinsic stimulus-responsive NO delivery system has thus become a research hotspot. The VEGF/eNOS pathway plays a critical role in vascular regeneration, while the Nrf2/NF-κB pathway is closely associated with antioxidant and anti-inflammatory mechanisms. This study constructs an FPG nanosystem combining fucoidan's natural anti-inflammatory and targeting properties with GSNO's NO-releasing capability for precise ultrasound-triggered therapy.

 

 

Research Methods and Experiments
The research team synthesized FPG nanoparticles through self-assembly methods containing fucoidan, GSNO, and PEG linkers. An endothelial dysfunction model was established using ox-LDL-stimulated HUVECs, with NO release triggered by ultrasound stimulation. RNA sequencing and Western blot analyses were employed to investigate NO release regulation of Nrf2, NF-κB, and VEGF/eNOS pathways. Animal experiments utilized ApoE−/− mice with high-fat diet-induced AS models to evaluate FPG+US effects on aortic plaque area, vascular wall thickness, and pulse wave velocity (PWV).

Key Conclusions and Perspectives

• Successfully synthesized FPG nanosystem with ultrasound-responsive controlled NO release capability, where release quantities can be regulated through ultrasound power density, concentration, and irradiation duration.
• In the ox-LDL-induced HUVEC model, FPG+US significantly reduced secretion of IL-6, IL-1β, and TNF-α while decreasing ROS and ONOO− levels, thereby enhancing cell migration and tubular structure formation.
• Animal experiments demonstrated FPG+US treatment group significantly reduced aortic plaque area (0.10 ± 0.04% vs. HFD group 2.25 ± 0.10%, P=0.003), effectively maintaining vascular wall structural integrity and PWV stability.
• Western blot and RNA-seq analyses confirmed FPG+US modulates oxidative stress, inflammation, and vascular regeneration through Nrf2 activation, NF-κB inhibition, and enhanced VEGF/eNOS pathway activity.
• Biosafety evaluation showed FPG exhibits no apparent toxicity in vitro or vivo, with therapeutic efficacy superior to statin drugs, demonstrating strong translational potential.

Research Significance and Prospects
This study provides a natural, targeted, and ultrasound-responsive NO delivery system for atherosclerosis-related endothelial dysfunction, establishing a foundation for future gene-editing animal models and pharmacological evaluation platforms. Next steps include combining gene-edited mice to investigate specific target roles in AS progression and verifying FPG's clinical translational potential using humanized models.

 

 

Conclusion
In summary, this research successfully constructed a natural ultrasound-responsive NO booster FPG that achieves controlled NO release in HUVECs through P-selectin targeting, effectively alleviating AS-related endothelial injury. The FPG+US treatment demonstrated significant improvements in oxidative stress and inflammatory microenvironment both in vitro and in vivo, while maintaining vascular repair capabilities and excellent biosafety. This study provides novel insights for precise NO delivery system design and experimental evidence for targeted therapy development and drug delivery platform construction in cardiovascular diseases.

 

Yuqiong Wang, Dong Meng, Yu Dong, Wen Gao, and Bo Tang. A natural ultrasound-triggered nitric oxide booster for endothelial dysfunction therapy. Chemical Science.