A HER2-targeted NIR-II fluorescent nanoprobe for precision diagnosis and treatment of HER2-positive breast cancer.

Abstract

e13026 Background: Breast cancer is the most common malignancy and a leading cause of cancer mortality worldwide. HER2-positive breast cancer, characterized by high aggressiveness and frequent therapy resistance, poses a significant clinical challenge. While antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (DS-8201) have improved treatment, the emergence of resistance limits their efficacy. Thus, developing innovative theranostic strategies to overcome these limitations is imperative. Methods: A stable DS-8201-resistant breast cancer cell line was established. RNA-seq analyzed resistance mechanisms and identified potential therapeutic targets. A novel actively targeted NIR-II fluorescent nanoprobe (DS-8201-ICG) was then constructed by conjugating DS-8201 with indocyanine green (ICG). This probe enables high-contrast deep-tissue imaging and real-time intraoperative navigation. Furthermore, based on immunosuppressive pathways identified via transcriptomics, the combined efficacy of the probe with immune checkpoint inhibitors was evaluated in vivo . Results: We established a DS-8201-resistant cell line with a stable resistant phenotype. Transcriptomics suggested the involvement of immune checkpoint pathways in resistance. The DS-8201-ICG nanoprobe exhibited excellent solubility, stable fluorescence, and high-affinity binding to HER2-positive cells. It showed favorable biocompatibility and safety in vitro and in vivo . In an orthotopic mouse model, the probe (2 mg/kg) provided clear tumor visualization 36 h post-injection via NIR-II imaging. Tumor fluorescence was 5-fold higher than normal tissue (TBR ≈ 5), enhancing margin delineation and micro-lesion detection to guide precise resection and potentially overcome resistance. Conclusions: We developed a novel HER2-targeted NIR-II imaging nanoprobe based on trastuzumab deruxtecan. This theranostic probe enables precise intraoperative visualization and resection of HER2-positive breast cancer, and its combination with mechanism-informed immunotherapy represents a novel strategy to overcome DS-8201 resistance.