Oncolytic virus-drug conjugates for increased viral replication efficiency and potentiated cancer chemoimmunotherapy.

Abstract

Oncolytic viruses (OVs) therapy is limited by poor systemic delivery efficiency to tumors, low intratumoral replication efficiency and insufficient immune activation against malignant cancers. Here, we report the autophagy-activated oncolytic adenoviruses (Ads)-doxorubicin (DOX) conjugates, combining the efficient co-delivery and viral intratumoral replication enhancement for potentiated chemoimmunotherapy. Ads-DOX conjugates are composed of Ads coated with a layer of biocompatible lipid membrane, and the autophagy-responsive DOX prodrugs inserted in the lipid membrane. The intravenous administration of Ads-DOX conjugates enables the efficient co-delivery of tumor lesions, where Ads can induce autophagy within the infected cancer cells and facilitate autophagic cell death. The intracellular autophagy triggered by Ads further promotes the release of DOX in an autophagy-responsive cascade manner, further overactivating intracellular autophagy. Meanwhile, the generated autophagosomes serve as the efficient sites for viral replication, thereby strengthening the replication efficiency of Ads in tumor cells and augmenting the intratumoral infiltration of cytotoxic T cells and the chemoimmunotherapeutic efficiencies. Consequently, the OVs-drug conjugates represent a potent translational approach to integrate virotherapy with chemotherapy for improved cancer chemoimmunotherapy.