Nanozyme‐Assisted Engineered Oncolytic Adenovirus for Improving Intratumoral Immune Deficiency and Enhancing Cancer Immunotherapy

ABSTRACT Oncolytic adenovirus (OA) exhibit tumor‐selective tropism, inducing direct oncolysis while simultaneously potentiating host immune responses against malignancies. However, the poor delivery efficiency of the virus targeting tumors and its limited immune activation capacity severely delays the therapeutic effect. This study proposes a kind of immunomodulator—OAencapsulated with gold nanozyme (AuA), possessing peroxidase‐like (POD) activity, named OA@AuA. This design uses bionic mineralization method for coating OAsurface antigens, delaying their clearance during circulation and thereby increasing viral accumulation at the tumor site. The OA@AuA can consume H 2 O 2 to generate reactive oxygen species (ROS), activate the cGAS‐STING pathway and promote the conversion of M2 macrophages to M1 macrophages. Subsequently, the tumor‐associated antigens and damage‐associated molecular patterns (DAMPs) were released, thus upregulating the expression of calreticulin (CALR) and high mobility group protein B1 (HMGB1), causing immunogenic cell death and activating tumor‐specific cytotoxic T cells to attack tumors, thereby reversing the tumor microenvironment. OA@AuA, as a potent immunomodulator, not only has good biocompatibility, but also breaks the immunosuppressive state in the tumor microenvironment, enhances immune infiltration in the tumor microenvironment, reverses immunosuppressive “cold” tumors into immunostimulatory “hot” tumors.