Oncolytic viruses (OVs) have been widely used as anticancer therapeutics because of their systemic immune responses during viral replication. However, the low enrichment of OVs within tumors and limited immune activation have hindered their clinical application. Herein, we proposed the concept of bacteria-assisted targeting of OVs to tumors, with liposome-cloaked oncolytic adenoviruses (OAs) conjugated onto tumor-homing Escherichia coli BL21 (designated as E. coli-lipo-OAs) for enhanced cancer immunotherapy. Notably, the enrichment of OAs transported by self-propelled bacterial microbe vehicles in E. coli-lipo-OAs in a nonsmall cell lung tumor can be potentiated by more than 170-fold compared with that of intravenously injected bare OAs. In vivo studies further revealed that E. coli-lipo-OAs administered intravenously significantly enhanced antitumor immunity through bacterial−viral-augmented immune responses. Our findings suggest that the self-driving microbe vehicle as a systemic delivery system for OVs can be a potent platform for developing future anticancer biotherapeutics at the clinical level.

Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor tropism, and spontaneous antiviral immune responses. Herein, a virus‐concealed tumor‐targeting strategy enabling OVs‘ delivery toward lung metastasis via systemic administration is described. The OVs can actively infect, be internalized, and cloak into tumor cells. Then the tumor cells are subsequently treated with liquid‐nitrogen‐shocking to eliminate the pathogenicity. Such a Trojan Horse‐like vehicle avoids virus neutralization and clearance in the bloodstream and facilitates tumor‐targeted delivery for more than 110‐fold virus enrichment in the tumor metastasis. In addition, this strategy can serve as a tumor vaccine and initiate endogenous adaptive antitumor effects through increasing the memory T cells and modulating the tumor immune microenvironment, including reducing the M2 macrophage, downregulating Treg cells, and priming T cells.

In article number 2212210, Funan Liu, Hongjun Li, Zhen Gu, and co-workers present an oncolytic virus therapy that can target metastasis after systemic administration. Tumor cells that have been pre-infected with an oncolytic virus serve as the delivery vehicle after pathogenicity has been eliminated by liquid nitrogen shock, but their metastasis-targeting ability is maintained by the integrity of cellular structure and surface protein preservation. This Trojan-horse-like method prevents virus neutralization and clearance in the bloodstream and improves tumor-specific delivery.