Ultrasound‐Manipulated Nanoplatform with Stable Hydrophobic Reservoirs for Spatiotemporal Controlled Renal Delivery of Therapeutic Gases

Abstract Targeted delivery of therapeutic gasotransmitters remains a fundamental challenge in gas therapy, particularly for highly water‐soluble molecules like hydrogen sulfide (H ₂ S) that undergo rapid systemic clearance and exhibit uncontrolled biodistribution. To overcome this limitation, a versatile nanoplatform constructed from amphiphilic polymers containing densely packed long alkyl chains that create stable hydrophobic gas reservoirs is developed. These nanostructures demonstrate unprecedented H ₂ S retention capabilities (>70% after 4 weeks at 4 °C), surpassing the stability limitations of current delivery systems. The integration of ultrasound responsiveness allows spatiotemporal regulation of nanoparticle migration and gas release via three key mechanisms: 1) Intensity‐dependent acoustic radiation forces enhance renal accumulation by 1.5‐fold; 2) Facilitated transendothelial transport enables delivery to proximal tubular epithelial cells within 2 h; and 3) Sustained intratubular retention (>8 h) maintains therapeutic H ₂ S levels. In cisplatin‐induced nephrotoxicity models, ultrasound‐activated H ₂ S‐loaded nanoparticles showed superior therapeutic efficacy, reducing tubular injury by more than 45% and accelerating functional recovery compared to conventional H ₂ S donors. This approach eliminates the need for bypassing complex donor chemistry while providing precise external control over gas release, offering a transformative strategy for gaseous nanomedicine.