Upconversion Luminescence‐Boosted Escape of DNAzyme from Endosomes for Enhanced Gene‐Silencing Efficacy

Abstract Despite the enormous potential of DNAzyme for gene therapy, its efficacy is hampered by the limited endosomal escape capability. Here, we develop a near‐infrared (NIR) light‐controlled DNAzyme delivery platform to achieve enhanced gene‐silencing efficacy. The nanoplatform is composed of therapeutic DNAzyme, photosensitizers (PSs) and upconversion nanoparticles (UCNPs) that can convert NIR light to visible light. The system allows NIR light‐activatable generation of cytotoxic reactive oxygen species due to the energy transfer from the UCNPs to PSs, which boosts the endosomal escape of DNAzyme for an improved gene‐silencing efficacy. We demonstrate that the nanocomposites represent a promising platform to integrate DNAzyme‐based gene therapy with NIR light‐triggered photodynamic therapy for combinational tumor treatment. This work highlights a robust approach to combat the current limitations of DNAzyme delivery systems.