Colon-targeted delivery of α-terpineol via ZIF-8 alleviates ulcerative colitis by anti-inflammatory and gut microbiota-metabolism modulation

Ulcerative colitis (UC) demands lifelong therapy, yet current regimens require daily high-dose administration that drives poor adherence and cumulative toxicity. Although α-terpineol (αTL) shows therapeutic efficacy in colitis, its oral application is limited by poor oral bioavailability and a lack of colon specificity. Rather than relying on sophisticated surface engineering, we encapsulated αTL within zeolitic imidazolate framework-8 (ZIF-8) during co-nucleation. This unmodified design permitted partial gastric release (∼46%) in gastric fluid and minimal release in intestinal fluid, with the remaining cargo subsequently released in the acidic environment of the inflamed colon. Oral administration of αTL@ZIF-8 resulted in colonic retention exceeding 24 h in DSS-induced colitis mice. Leveraging this colonic accumulation, an every-other-day regimen at 10 mg kg-1 achieved efficacy comparable to daily free αTL at 100 mg kg-1 or cyclosporine A at 60 mg kg-1. Mechanistically, αTL@ZIF-8 restored Claudin-1 and ZO-1 expression, enriched butyrate-producing genera and elevated butyrate levels, and uniquely modulated glutathione synthesis-related pathways. Safety evaluation in healthy mice showed no overt toxicity under this regimen. This formulation reduces premature drug exposure in the upper gastrointestinal tract and allows more αTL to reach the acidic environment of the inflamed colon. These features enable a low-dose, every-other-day oral regimen that decouples therapeutic efficacy from dosing frequency, positioning it as a promising candidate for long-term UC management.