A Spatiotemporally Controlled Gene‐Regulation Strategy for Combined Tumor Therapy Based on Upconversion Hybrid Nanosystem

Abstract

AbstractThe lack of precise spatiotemporal gene modulation and therapy impedes progress in medical applications. Herein, a 980 nm near‐infrared (NIR) light‐controlled nanoplatform, namely URMT, is developed, which can allow spatiotemporally controlled photodynamic therapy and trigger the enzyme‐activated gene expression regulation in tumors. URMT is constructed by engineering an enzyme‐activatable antisense oligonucleotide, which combined with an upconversion nanoparticle (UCNP)‐based photodynamic nanosystem, followed by the surface functionalization of triphenylphosphine (TPP), a mitochondria‐targeting ligand. URMT allows for the 980 nm NIR light‐activated generation of reactive oxygen species, which can induce the translocation of a DNA repair enzyme (namely apurinic/apyrimidinic endonuclease 1, APE1) from the nucleus to mitochondria. APE1 can recognize the basic apurinic/apyrimidinic (AP) sites in DNA double‐strands and perform cleavage, thereby releasing the functional single‐strands for gene regulation. Overall, an augmented antitumor effect is observed due to NIR light‐controlled mitochondrial damage and enzyme‐activated gene regulation. Altogether, the approach reported in this study offers high spatiotemporal precision and shows the potential to achieve precise and specific gene regulation for targeted tumor treatment.