Virus-protein corona replacement strategy to improve the antitumor efficacy of intravenously injected oncolytic adenovirus

Abstract

Intravenous administration of oncolytic adenoviruses(OVs) is ahopeful tumor therapeutic modality. However, the sharp clearance ofOVs by the immune system dampens its effectiveness. Many studies haveattempted to extend the circulation of intravenously administeredOVs, almost all by preventing OVs from binding to neutralizing antibodiesand complements in the blood, but the results have not been satisfactory.In contrast to previous conclusions, we found that the key to improvingthe circulation of OVs is to prevent the formation of the virus-proteincorona rather than simply preventing the binding of neutralizing antibodiesor complements to OVs. After identifying the key protein componentsof the virus-protein corona, we proposed a virus-protein corona replacementstrategy, where an artificial virus-protein corona was formed on OVsto completely prevent the interaction of OVs with key virus-proteincorona components in the plasma. It was found that this strategy dramaticallyprolonged the circulation time of OVs by over 30 fold and increasedthe distribution of OVs in tumors by over 10-fold, resulting in superiorantitumor efficacy in primary and metastatic tumor models. Our findingprovides a perspective on intravenous delivery of OVs, shifting thefocus of future studies from preventing OV binding with neutralizationantibodies and complements to preventing OVs from interacting withkey virus-protein corona components in the plasma.