A Targeted Nanozyme for STING Activation Improves BiTEs Therapy Outcomes in Colorectal Cancer

ABSTRACT Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality worldwide, with limited efficacy of conventional therapies due to immunosuppressive tumor microenvironments and high recurrence. While bispecific T‐cell engagers (BiTEs) show promise by engaging T cells against tumors, their clinical translation is hindered by poor stability, on‐target off‐tumor effect, and systemic toxicity. Herein, we develop a tumor‐targeted nanozyme (MnO ₂ ‐dsDNA@BiTE/APT) that co‐delivers hydrolytically stable double‐strand DNA (dsDNA: a STING agonist) and PD‐L1/CD3 BiTE to overcome these limitations. The nanozyme leverages MnO ₂ as a carrier for dsDNA, surface‐loaded with BiTE via polyphenol‐protein coordination, and functionalized with an aptamer (APT) for active targeting. Upon systemic administration, the nanozyme accumulates in tumors, releasing dsDNA, Mn ²⁺ , and BiTE. The synergistically activates the STING pathway to remodel the immunosuppressive microenvironment and enhances T cell‐mediated cytotoxicity. This strategy represents a promising approach for potentiating immunotherapy in CRC by integrating innate immune activation with adaptive T cell engagement.