Mesoporous silica nanoparticles with redox-responsive surface linkers for charge-reversible loading and release of short oligonucleotides

Aimed at high loading and controlled release of oligonucleotides with short sequences of base-pairs, a novel series of mesoporous silica nanoparticles with three different pore sizes (3.5–5.0 nm) but the same cleavable surface linkers (MSN-Linker-Cys) were synthesized. The small particle size (70 nm) with radially aligned pore structure and the well-defined surface linkers terminated with amino groups led to unprecedentedly high adsorption capacities of a model oligo DNA (21 bp in length) into MSN-Linker-Cys particles, where MSN with a medium pore size of 4.5 nm exhibited the highest adsorption capacity (190 mg g⁻¹). The electrostatic attraction forces between amino groups on the surfaces and phosphate groups of DNA led to N/P ratios less than 1 in the particles, and retained the loaded DNA molecules inside the particles albeit with some degree of premature release observed. Triggered by the presence of reducing agents mimicking those found inside cells, the disulfide bond was shown to be cleaved in the organic linkers, generating a thiol group terminated surface. As a consequence, the most efficient release of DNA was found for MSN-Linker-Cys at neutral pH. A sustained responsive release with lower premature release ratio was obtained after a PEG polymer was conjugated to the free amines on the particle surface post adsorption of DNA. This nanocarrier design was based on the understanding and tuning of the molecular interactions between oligonucleotides and the cationic linkers. Thus, it is expected to lay the possibility for the development of innovative and strategic approaches for advancing related gene delivery technology.