Genetically Engineered Cell Membrane Nanovesicles for Oncolytic Adenovirus Delivery: A Versatile Platform for Cancer Virotherapy.

Currently, various oncolytic adenoviruses (OA) are being explored in both preclinical and clinical virotherapy. However, the pre-existing neutralizing antibodies (nAbs) and poor targeting delivery are major obstacles for systemically administered OA. Therefore, we designed bioengineered cell membrane nanovesicles (BCMNs) that harbor targeting ligands to achieve robust antiviral immune shielding and targeting capabilities for oncolytic virotherapy. We employed two distinct biomimetic synthetic approaches: the first is based on in vitro genetic membrane engineering to embed targeting ligands on the cell membrane, and the second is based on in vivo expression of CRISPR-engineered targeting ligands on red-blood-cell membranes. The results indicate that both bioengineering approaches preserve the infectivity and replication capacity of OA in the presence of nAbs, in vitro and in vivo. Notably, OA@BCMNs demonstrated a significant suppression of the induced innate and adaptive immune responses against OA. Enhanced targeting delivery, viral oncolysis, and survival benefits in multiple xenograft models were observed without overt toxicity. These findings reveal that OA@BCMNs may provide a clinical basis for improving oncolytic virotherapy by overcoming undesired antiviral immunity and enhancing cancer cell selectivity via biomimetic synthesis approaches.