Logic‐Gated HSV‐TK/GCV Suicide Gene Circuit for Triple‐Negative Breast Cancer

ABSTRACT Triple‐negative breast cancer (TNBC) remains a major clinical challenge, owing to its molecular complexity, therapeutic resistance, and lack of specific druggable targets. The herpes simplex virus thymidine kinase/ganciclovir (HSV‐TK/GCV) suicide gene therapy system has shown promise in cancer treatment, but its clinical applicability is limited by off‐target cytotoxicity. Here, we developed a br east c a ncer‐specific s uicide gene circuit (BRAS) that integrates the screened cancer‐specific promoters RRM2 and MAFK with a microRNA specific to nontumor cells, utilizing the distinct molecular profiles of tumor and nontumor cells. This multi‐input logic gate circuit enables precise, specific expression of HSV‐TK in breast cancer cells with hardly expression in normal cell. We show that BRAS selectively induces apoptosis in patient‐derived TNBC cells while sparing normal cells. In two orthotopic breast cancer models, BRAS significantly suppressed tumor growth without affecting body weight or general health, underscoring its therapeutic potential. This approach intelligently combines molecular signals from both cancerous and healthy cells to precisely regulate therapeutic gene expression, making it a promising platform for the next‐generation cancer therapy.