Water wetting behavior in nanometer dimensions is of great importance to the signal transmission and substance transport of organisms, e.g., aquaporins on cell membranes. A biological channel can control the transport of water and ions by regulating channel wettability, which results from the transition between the intrinsic hydrophobic state and the stimulus-induced hydration state. Inspired by aquaporins in nature, herein, a biomimetic free-blocking on-demand delivery system is proposed, which is constructed by controlling the wettability of the inner surface of nanochannels of mesoporous silica nanoparticles (MSNs). Such a system is completely different from the traditional physically occluding pore controlled release system. It circumvents the use of other extra capping agents, thus overcoming the limitations of the traditional nano “gate” blockage system with inherent instability, poor plugging capability and low biocompatibility. Additionally, further applications in drug delivery have shown that this system can selectively release entrapped drugs in beta cells triggered by intracellular glucose in a controlled manner but not in normal cells. This hydrophobic gating drug delivery system with simple and effective performance provides a new opportunity for constructing a mass transport platform from the perspective of surface wettability.