Bioinspired nanoparticles deliver DNase I to attenuate ulcerative colitis by degrading NETs and modulating PTGS2-mediated ER stress

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized clinically by recurrent abdominal pain and bloody diarrhea, for which there is currently a lack of curative therapeutic strategies. In recent years, neutrophil extracellular traps (NETs) have been identified as playing a key role in the pathogenesis of UC, emerging as a potential therapeutic target. Although deoxyribonuclease I (DNase I) can exert therapeutic effects by degrading the DNA backbone of NETs, its clinical application is limited by inherent drawbacks, including poor in vivo stability, low bioavailability, and inefficient penetration of biological barriers. Herein, this study constructed a biomimetic membrane-based nanodelivery system. Initially, zeolitic imidazolate framework-8 (ZIF-8) was used to encapsulate DNase I, forming ZD nanoparticles to enhance enzymatic stability. Subsequently, these nanoparticles were coated with bacterial outer membrane vesicles (BOMVs), yielding the final BVZD composite system, designed to improve targeting to inflammatory sites. The BVZD system exhibited suitable particle size, good biocompatibility, and a demonstrated ability to specifically accumulate in the inflamed intestinal regions of a UC model. Both in vitro and in vivo experiments confirmed that BVZD effectively degraded NETs, suppressed endoplasmic reticulum stress (ERS) by downregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), and promoted the repair of the intestinal epithelial barrier. These findings highlight the promising therapeutic potential of BVZD for the treatment of UC.