Near‐Infrared Light‐Triggered Cascade Nanosystems for Spatiotemporally Controlled Gene‐Silencing and Gas Synergistic Cancer Therapy

Despite the tremendous potential of DNAzymes in gene therapy, achieving gene regulation with spatiotemporal precision and satisfactory efficacy remains a key challenge. Herein, we developed a near-infrared light (NIR)-triggered cascade effect system that enables precise spatiotemporal gene silencing and gas-synergistic cancer therapy. This nanoplatform was constructed using an enzyme-activatable DNAzyme, a nitric oxide (NO) precursor, and upconversion nanoparticles (UCNPs). The UCNPs act as light converters, facilitating the precursor to produce NO under NIR light irradiation, while the generated NO not only participates directly in gas therapy but also induces the upregulation of cytoplasmic APE1 level, resulting in enhanced DNAzyme activation and spatially controlled gene silencing. By leveraging this mechanism, cascade effects mediated gas-gene synergistic therapy is achieved through the combination of NIR light-controlled NO release and APE1-activatable gene therapy. We demonstrated that this nanoplatform enables enhanced anti-tumor effects both in vitro and in vivo. This strategy represents a critical step forward in the quest for highly targeted and efficient cancer treatments.