An opposite pH-responsiveness "gating" strategy: Intelligent sporopollenin exine armor for targeted therapy of...

Conventional therapy for ulcerative colitis (UC) is often limited by insufficient colonic targeting, short local retention and poor cellular drug uptake at lesion sites. Here, we develop a biomimetic colon-targeted delivery system based on an opposite pH-responsive "gating" strategy. Chrysanthemum sporopollenin (spo) microcapsules with a characteristic spiny architecture serve as the core carrier. Spo exhibits acid-induced contraction and alkali-induced expansion, with germinal apertures opening progressively as pH increases. In contrast, chitosan-butyrate complex (CBC) swells into a gel under acidic conditions but contracts and precipitates in alkaline environments. After drug loading into the spo, surface coating with CBC seals the germinal apertures, constructing an intelligent gate. In gastric fluid, the CBC layer gels and blocks apertures to prevent premature drug release. In intestinal fluid, CBC contracts and precipitates to open the gate; meanwhile, spo expands to further widen germinal apertures and facilitate drug release. The spiny morphology of spo, combined with the mucoadhesive properties of chitosan and active targeting of butyrate, collectively enhances intestinal adhesion and retention, enabling precise colonic drug release and accumulation. Mesalazine is formulated into liposomes to improve aqueous solubility and stability, which enhances cellular uptake and bioavailability, thereby exerting synergistic anti-inflammatory effects with butyric acid at inflamed sites. The chrysanthemum sporopollenin-based gated microcapsules exhibit favorable pH-responsive release, enhanced mucoadhesion and potent synergistic anti-inflammatory activity. This work provides a promising multifunctional targeted delivery strategy for UC therapy and establishes a novel, versatile design concept termed the opposite pH-responsive dual-gating mechanism, which supports the development of oral colon-targeted carriers capable of navigating complex gastrointestinal environments.