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.
Qin et al. (Thu,) studied this question.