Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma.

Glioblastoma (GBM) represents the most aggressive primary brain tumor, and urgently requires effective treatments. Oncolytic adenovirus (OA) shows promise as a potential candidate for clinical antitumor therapy, including in the treatment of GBM. Nevertheless, the systemic delivery of OA continues to face challenges, leading to significantly compromised antitumor efficacy. In this study, we developed an innovative approach by encapsulating CXCL11-armed OA with tannic acid and Fe³⁺ (TA-Fe³⁺) to realize the systemic delivery of OA. The nanocarrier's ability to protect the OA from elimination by host immune response was evaluated in vitro and in vivo. We evaluated the antitumor effect and safety profile of OA@TA-Fe³⁺ in a GBM-bearing mice model. OA@TA-Fe³⁺ effectively safeguarded the virus from host immune clearance and extended its circulation in vivo. After targeting tumor sites, TA-Fe³⁺ could dissolve and release Fe³⁺ and OA. Fe³⁺-induced O₂ production from H₂O₂ relieved the hypoxic state, and promoted OA replication, leading to a remarkable alteration of tumor immune microenvironment and enhancement in antitumor efficacy. Moreover, the systemic delivery of OA@TA-Fe³⁺ was safe without inflammation or organ damage. Our findings demonstrated the promising potential of systemically delivering the engineered OA for effective oncolytic virotherapy against GBM.