Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy.

Systemic delivery of oncolytic viruses (OVs) is limited by neutralizing antibodies and poor intratumoral bioavailability. Here we developed genetically engineered, immune-compatible cell membranes expressing a chimeric antigen receptor to cloak OVs, creating a tumor-targeted viral delivery platform (iNV-GOV) that shields virions from immune recognition while guiding them to tumors. The OV payload encodes an N-terminal gasdermin under a heat-shock promoter enabling ultrasound-induced mild hyperthermia to trigger tumor-specific pyroptosis, accelerate oncolysis and promote rapid viral release from lysed tumor cells, thereby amplifying infection of neighboring tumor populations. Following systemic administration, iNV-GOV efficiently targets and infects tumor cells, induces pyroptosis upon ultrasound activation and elicits robust antitumor immunity in patient-derived xenograft models in humanized mice. Collectively, this systemically injectable, tumor-targeted OV platform enables rapid and continuous intratumoral viral propagation and represents a promising strategy for treating a wide range of cancers.