Synergetic Gating of Metal-Latching Ligands and Metal-Chelating Proteins for Mesoporous Silica Nanovehicles to Enhance Delivery Efficiency

Stimuli-responsive drug delivery systems are highly desirable for improved therapeutic efficacy and minimized adverse effects of drugs. Mesoporous silica nanoparticles (MSNs) functionalized with pentadentate ligands, N-(3-trimethoxysilylpropyl)ethylenediamine triacetate (TSP-DATA), in the presence of metal ions with and without myoglobin (Mb)-containing surface-accessible histidine residues, were constructed for pH-triggered controlled release. The DATA ligands immobilized on the MSN pore outlets could encapsulate cargo within the pores by metal latching across pore openings, and release efficiency increased with the increase of surface density of the DATA ligands. The release efficiencies for the metal-chelating protein nanogates, through multiple-site binding of Mb with the metal-chelating ligands, were higher than those for the metal-latching ligand nanogates but were almost independent of surface density of the ligands investigated. Both the metal-latching ligands and the metal-chelating proteins played a synergetic role in gating MSNs for high-loading drug delivery and stimuli-responsive controlled release. The constructed Mb-Cu2+-gated MSN delivery system has promising applications in targeted drug therapy of tumors.