OICC Press Journal of Nanostructure in Chemistry 2193-8865 16 3 2026 06 30 Design of a Calcium-Triggered Nanostructured Delivery System for Controlled In Vitro Release of Trypsin Inhibitor 10.57647/jnsc.2026.1603.11 EN Yugang Qin Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Wenxuan Zhang Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Bolun Zhang Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Gaoxue Li Department of Gastroenterology, Shouguang People’s Hospital, Shouguang, Shandong, 262702, China Yongbiao Ma Department of Pancreatic Surgery Weifang People’s Hospital, Weifang, Shandong, 261100, China Qiang Zhang Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Xiaojun Wei Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Yang Xu Department of Hepatobiliary Surgery, Aerospace Center Hospital, Beijing, 100049, China Journal Article 2026 06 30 We report a mesoporous silica nanoparticle platform that exploits physiological divalent ions as a benign trigger to control stage-specific protein release under gastrointestinal-mimicking in vitro conditions, using soybean trypsin inhibitor as a model cargo. Spherical pore-expanded MSNs (~300 nm, pore diameter ~3.8 nm, BET surface area ~800 m2/g) were synthesized, loaded with up to 15.6 wt% inhibitor at 75% encapsulation efficiency, and then capped with an ~8 wt% PVA–borate nanogel gate to yield PB-MSN composites containing 14.5 wt% protein. Structural, textural and dispersion analyses confirmed that the coating partially occluded pore mouths while preserving the mesoporous framework and improving colloidal stability. In a two-stage simulated gastrointestinal protocol, PB-MSNs leaked only 3.8 ± 0.5% cargo after 2 h in pH 1.2 medium, whereas uncoated MSNs released 68 ± 5% under the same conditions. Subsequent exposure to pH 7.4 buffer containing 10 mM CaCl2 triggered a rapid burst, with cumulative release reaching ~40% within 0.5 h, 78 ± 3% at 4 h and 88 ± 4% at 8 h; in Ca2+-free buffer, release remained ≤12.3 ± 1.5% over 8 h, demonstrating a sharp ion-dependent on/off effect. Trypsin activity assays showed that inhibitor liberated under triggering conditions suppressed trypsin activity to a level comparable to free inhibitor, while SGF supernatants exhibited negligible inhibition, indicating substantial retention of inhibitory function in a reductionist activity assay and minimal gastric-phase leakage. The combined data establish PVA–borate-gated MSNs as a modular, ion-responsive platform that decouples protection in acid from fast deployment in near-neutral media. While calcium-responsive carriers and borate-based dynamic networks are well established in other delivery and hydrogel contexts, the present work translates this chemistry into an MSN pore-gating architecture in which Ca²⁺ acts as a competitive borate-binding trigger to dismantle a nanoscale sacrificial gate and thereby generate a sharp ‘off/on’ release response under GI-mimicking conditions.