Targeted delivery of nebivolol via lactoferrin-modified liposomes inhibits NEK7-mediated pyroptosis to ameliorate inflammatory bowel disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder where pyroptosis of intestinal epithelial cells, driven by the NEK7/NLRP3 axis, is a key pathological feature. This study aimed to identify a novel inhibitor of NIMA-related kinase 7 (NEK7) and develop a targeted delivery system to enhance its therapeutic efficacy for IBD. Through a virtual screening of FDA-approved drugs, nebivolol was identified as a potent NEK7 inhibitor. Subsequent biochemical and cellular assays confirmed that nebivolol directly binds to the LYS64 site of NEK7, inhibiting its kinase activity and disrupting its interaction with NLRP3. This inhibitory action was shown to protect intestinal epithelial cells from pyroptosis in vitro and to significantly ameliorate disease symptoms, histological damage, and molecular markers of pyroptosis in a chronic DSS mouse model of colitis, with a high safety profile. To enhance therapeutic efficacy and specificity, a quantitatively characterized targeted delivery system of lactoferrin-modified liposomes loaded with nebivolol (LF-Lipo@N) was developed. This system demonstrated superior uptake by intestinal cells via lactoferrin and lactoferrin receptors (LFRs) interaction and a more potent anti-pyroptotic effect in vitro. Crucially, the quantitative biodistribution analysis showed that the targeted LF-Lipo@N system significantly accumulated in the colon in vivo, leading to a significantly enhanced therapeutic effect compared to free nebivolol while eliminating systemic side effects on heart rate. In conclusion, the targeted delivery of nebivolol via lactoferrin-modified liposomes represents a promising and effective strategy for treating IBD by specifically inhibiting NEK7-mediated intestinal pyroptosis.