A cascade-activated nanotheranostic platform for MRI-guided hydrogen sulfide therapy and microenvironment remodeling...

Clinical implementation of hydrogen sulfide (H₂S) therapy for inflammatory bowel disease (IBD) is hindered by the lack of delivery systems capable of stable, intestine-targeted, and endogenous thiol-independent gas release. To address this, we introduce TB-MnS@S100, a fully synthetic, orally deliverable nanotheranostic platform that decouples H₂S release from host biochemistry while enabling real-time imaging. The system comprises a tributyrin-manganese sulfide (TB-MnS) core encapsulated in a pH-responsive Eudragit S100 shell, which remains intact in the upper gastrointestinal tract but dissolves in the alkaline intestinal environment. This platform fully leverages lipases naturally present in vivo-lipase-mediated hydrolysis of tributyrin generates butyrate, whose intracellular metabolism acidifies the local microenvironment, thereby triggering controlled MnS decomposition. This cascade ingeniously exploits endogenous lipase activity to achieve stable and sustained hydrogen sulfide (H₂S) release, accompanied by Mn²⁺ production, providing T₁-weighted magnetic resonance imaging (MRI) contrast enhancement without relying on exogenous activators. In a murine model of inflammatory bowel disease induced by dextran sulfate sodium, TB-MnS@S100 achieves synergistic butyrate-H₂S therapy, suppressing oxidative stress, downregulating pro-inflammatory cytokines, restoring epithelial tight junction integrity, and rebalancing gut microbiota. The released Mn²⁺ also enables non-invasive MRI monitoring of inflammation and treatment response, establishing a closed therapeutic-monitoring loop. This work presents an exogenous activator-independent H₂S delivery strategy that advances nanotheranostics for IBD by integrating mechanism-guided therapy with real-time imaging.