Near-Infrared Titania Nanoparticle-Based Photoimmunotherapy via Tumor-Microenvironment-Responsive Gene Editing of SerpinB9 for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a heterogeneous disease with multiple biological subtypes, offering poor clinical outcomes. No targeted therapy was approved for TNBC due to lack of tumor-specific targets. Here, we identify SerpinB9 as a vulnerability target for immunomodulatory TNBC tumors, suggesting that gene editing of SerpinB9 via the CRISPR/Cas9 system may be a viable approach to immunomodulatory TNBC-targeted therapy. To increase bioavailability and improve the delivery efficiency of gene editing, we designed glutathione-responsive nanoparticles to deliver Cas9 ribonucleoprotein targeting SerpinB9 (TiO2-x@Cas9-RNP@HA). Under near-infrared light irradiation, TiO2-x can produce both photodynamic therapy (PDT) and photothermal therapy (PTT) effects. PTT can induce tumor cell ablation and immunogenic cell death. PDT can produce ROS to induce cell killing and downregulation of SerpinB9. Inhibition of SerpinB9 expression with nanoparticles (TiO2-x@Cas9-RNP@HA) combined with near-infrared titania phototherapy can synergistically inhibit tumor growth. These results demonstrate the potential of near-infrared titania nanoparticle-based phototherapy and precise SerpinB9-targeted therapies in immunomodulatory TNBCs.