Leukocyte Esterase-Activated Nanoconjugates Enables Precise Local Therapy of Ulcerative Colitis via Inflamed Tissue-Selective Drug Delivery.

Leukocyte esterase (LE), markedly upregulated in inflamed colonic tissues, offers a unique enzymatic trigger for selective drug activation in ulcerative colitis (UC). To exploit this pathological hallmark, we developed LE-activated nanoconjugates that enable inflamed tissue-selective drug delivery as a strategy to achieve precise local therapy for UC. Dexamethasone (DEX) was covalently conjugated to poly(lactide-co-glycolide) (PLGA) via ester bonds to form nanoconjugates (DPNCs) with suppressed drug release during gastrointestinal transit. These nanoconjugates accumulated in inflamed colonic tissues via the epithelial enhanced permeability and retention (eEPR) effect and selectively released DEX in response to elevated LE activity. In a dextran sulfate sodium-induced colitis model, orally administered DPNCs achieved superior colonic drug accumulation, minimized systemic distribution, and significantly improved therapeutic outcomes compared with free DEX. These findings highlight the potential of LE-activated nanoconjugates as an effective oral platform for precise and safe treatment of UC.