Oral microalgae-ROS-responsive hierarchical targeting delivery system for precision therapy of ulcerative colitis

Ulcerative colitis (UC) is a chronic, non-specific inflammatory bowel disease. Currently, the lack of precise oral colon-targeted delivery systems prevents current drugs from effectively accumulating at inflamed sites, leading to unsatisfactory therapeutic outcomes. Although anthocyanins possess great potential to mitigate oxidative damage and inflammation cascade, their poor gastrointestinal stability and oral absorption limit clinical application. To address this challenge, we innovatively propose a hierarchical targeted nano-delivery system (SP@PRA@PCT) that combines Spirulina platensis (SP) with reactive oxygen species (ROS)-responsive nanoparticles loaded with purple radish anthocyanin (PRA), aiming to enhance gastrointestinal stability and achieve precise retention in inflamed regions. SP@PRA@PCT exhibits hierarchical targeting properties: the unique helical morphology of SP facilitates its retention in intestinal villi, thereby prolonging intestinal residence time; the SP-loaded PRA@PCT (with an encapsulation efficiency of 75.5% and a drug loading content of 4.03%) can further target intracellular mitochondria and specifically release PRA in response to ROS within the inflammatory microenvironment. In vitro studies demonstrate that this system effectively scavenges excessive ROS, alleviates mitochondrial dysfunction, promotes epithelial cell migration, regulates the expression of inflammatory cytokines, and inhibits apoptosis. On DSS-induced colitis in mice, SP@PRA@PCT significantly prolongs intestinal retention time to 48 h and achieves superior therapeutic efficacy compared to free PRA or non-targeted controls, as evidenced by preserved colon length, decreased disease activity index, restored intestinal barrier integrity, and effective modulation of gut microbiota balance through increased abundance of beneficial bacteria. In summary, this oral microalgae-based ROS-responsive nano-delivery system, which integrates ROS-responsive release, mitochondrial targeting, and microalgae-mediated bioadhesion, effectively overcomes the key bottleneck of poor oral absorption, providing a highly promising strategy for the oral delivery of natural extracts to manage colitis.