Antioxidant Enzymes Sequestered within Lipid–Polymer Hybrid Nanoparticles for the Local Treatment of Inflammatory Bowel Disease

The local treatment of inflammatory bowel disease (IBD) by enzyme therapeutics is challenging owing to hostile environments in the gastrointestinal tract, leading to the hydrolysis and enzymatic degradation of labile proteins. In this study, safe and efficient local drug delivery systems were developed by antioxidant superoxide dismutase (SOD) sequestered within lipid-polymer hybrid nanoparticles through sequential self-assembly processes. Interestingly, we found that the sequestered SOD exhibited long-term enzymatic stability and comparable biological activity to the enzymes in the native form, probably owing to particle encapsulation providing a physical barrier to prevent the enzymolysis of proteins. We demonstrated that nanoparticle-based local drug delivery systems showed excellent mucus-penetrating ability and inflammation-targeting properties, owing to the particle surface with a poly(ethylene glycol) (PEG) coating and folate functionalization, thus improving mucosal retention time and drug delivery efficiency within the colorectal region. Furthermore, SOD-containing lipid-polymer hybrid nanoparticles could effectively mitigate inflammatory responses by regulating the secretion of inflammation-associated cytokines, thus increasing therapeutic outcomes in colitis mice through intrarectal administration. The findings indicated that antioxidant enzymes sequestered within lipid-polymer hybrid nanoparticles might be potential enzyme therapeutics for the local treatment of some inflammatory diseases in the near future.