A hierarchically assembled oral formulation with drug-convertible carriers for targeted ulcerative colitis therapy through a three-pronged strategy

Abstract Ulcerative colitis (UC) is a serious global disease whose incidence has been increasing. Currently, its clinical therapies are mainly anti-inflammatory agents and still result in a remission rate of less than 60%. Therefore, developing novel oral delivery systems to achieve multitarget therapy for UC treatment remains crucial. This study develops a hierarchically assembled oral delivery formulation for targeted UC therapy through a three-pronged strategy, including anti-inflammatory effects, barrier restoration, and microbiota modulation. Specifically, berberine and dehydrocostus lactone (BD), which are compatible bioactive molecules derived from herbs, are embedded into nano/microscale protein aggregates (PA) for prolonged retention and sustained drug release. Subsequently, BD-embedded PA (BD/PA) is encapsulated by sodium alginate microspheres (@SA) to yield BD/PA@SA for colon-targeted delivery. The coordination of components in BD/PA@SA considerably extends the drugs’ bioavailability up to 1 week at approximately 1/20 original dosage and targets the three most important pathological features (inflammation, mucosal barrier damage, and gut microbiota disorders) of UC to achieve excellent three-pronged efficacy. Importantly, the delivery carriers (PA and @SA) can be converted into short-chain fatty acids through microbial metabolism to treat UC, as confirmed by the microbiome, metabolomics, and transcriptomics analyses. This work presents a hierarchically assembled oral formulation effective against UC, utilizing carriers that can achieve 1-week retention and sustained drug release, along with the drug-convertible capacity to maximize therapeutic efficacy.