Four‐Pronged Nanomotor Strategy Achieves Efficient TNBC Treatment via Synergistic Chemo‐Photothermal‐Immune Therapy

Abstract Triple‐negative breast cancer (TNBC) is a highly aggressive subtype lacking specific molecular targets, rendering conventional therapies ineffective. Key obstacles in treatment include elevated intracellular glutathione (GSH), poor drug penetration, and an immunosuppressive tumor microenvironment. Herein, a four‐in‐one Janus‐type near‐infrared (NIR)‐driven nanomotor is employed, composed of copper selenide (Cu 2‐x Se) asymmetrically coated with disulfide‐bridged periodic mesoporous organosilica (PMO) and loaded with doxorubicin (DOX), termed C&P‐DOX. Upon NIR irradiation, Cu 2‐x Se generates localized hyperthermia, propelling the nanomotor into deep tumor regions due to their asymmetrical structure. After internalization, high GSH triggers disulfide cleavage, promoting GSH depletion, disrupting redox homeostasis, and achieving controlled DOX release. The uniform distribution and effective release of DOX throughout the tumor enhance cytotoxic effects, inducing significant tumor cell apoptosis. In addition, the synergistic mild photothermal therapy and chemotherapy induce immunogenic cell death, releasing damage‐associated molecular patterns and tumor‐associated antigens that promote dendritic cell maturation and T‐cell activation. This process transforms the tumor immunosuppressive microenvironment into an immunogenic environment, enhancing cytotoxic T lymphocyte infiltration and synergizing with PD‐L1 antibody therapy to amplify immune responses. The four‐pronged C&P‐DOX nanomotor effectively penetrates deep tumors, depletes GSH, combines tumor treatment, and enhances immunotherapy outcomes, integrating active synergistic chemo‐photothermal‐immune therapy for improved TNBC treatment.