NATCANCER-A16341B 1 2 iNV GOV 3 4GOV

Oncolytic viruses (OVs) are replication-competent viruses that selectively infect tumor cells and induce anti-tumor responses. However, systemic delivery is limited by neutralizing antibodies and poor intratumoral bioavailability. We developed iNV-GOV, a tumor-targeted, low-immunogenic platform that cloaks OVs with genetically engineered, immune-compatible cell membranes expressing a chimeric antigen receptor, shielding virions from immune recognition and guiding them to tumors. The payload encodes an N-terminal gasdermin under a heat-shock promoter, and ultrasound-induced mild hyperthermia drives gasdermin expression, triggering tumor-cell pyroptosis, enabling accelerated oncolysis and rapid release of OVs from lysed tumor cells which subsequently infect neighboring tumor cell populations. After systemic administration, iNV-GOV efficiently targets and infects humanized orthotopic patient-derived xenografted tumors, ultrasound activation induces pyroptosis and elicits robust antitumor immunity. Thus, the systemically injectable, tumor-targeted OVs that are capable of rapid and continuous infection of tumor cells represent a promising oncolytic virotherapy for treating a wide range of cancers.