Abstract

The broader clinical application of Bispecific T-cell engagers (BiTEs) is hindered by their short half-life, on-target off-tumor toxicity, and limited therapeutic effect for solid tumors. Herein, we constructed a bimetallic-enriched triple-kill nanobomb manganese/Co 2+ -dopamine@BiTE/HPT (MnO 2 /Co-DA@BiTE/HPT) based on metal-polyphenol to improve the immunosuppressive tumor microenvironment by activating innate and adaptive immunity, thereby enhancing the treatment efficacy of BiTEs (PD-L1/CD3). A hyaluronic acid-modified PD-L1 aptamer (HPT) was introduced to improve the active targeting of the nanobombs and bind with PD-L1 overexpressing colorectal cancer. Bimetallic (Mn 2+ /Co 2+ ) activated the STING pathway; simultaneously, photothermal therapy (PTT) induces DNA fragmentation to cooperate with bimetallic to amplify the STING signal to “heat” the “cold” tumor microenvironment. The “hot” tumor with a large amount of T-cell infiltration facilitated BiTE recruitment of T cells to kill tumor cells. Furthermore, the efficient therapeutic potency of the triple-kill nanobombs (STING, BiTE, and PTT) was determined in subcutaneous colorectal cancer, distal, lung metastasis, and postoperative recurrence models, which indicated that MnO 2 /Co-DA@BiTE/HPT could improve the immune microenvironment, produce long-term immune memory, inhibit tumor growth, and prevent tumor recurrence and metastasis.