A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy

The dearth of technologies that allow gene modulation and therapy with high spatiotemporal precision remains a bottleneck in biomedical research and applications. Here we present a near-infrared (NIR) light-controlled nanosystem that allows spatiotemporally controlled regulation of gene expression and thus combinational tumor therapy. The nanosystem is built by engineering of an enzyme-activatable antisense oligonucleotide and further combination with an upconversion nanoparticle-based photodynamic system and a mitochondria localization signal. The system relies on photodynamic effect-induced translocation of a DNA repair enzyme from nucleus into mitochondria, which enables spatially selective gene regulation via enzymatic reactions. We demonstrate that the NIR light-induced mitochondrial photodamage and gene regulation enable enhanced antitumor effect. Our approach may enable the specific gene regulation and tumor treatment with high precision both spatially and temporally.