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

Abstract

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.

Extracellular vesicle-based drug delivery systems for cancer treatment

“…In addition to small molecule therapeutics, pre-loading strategies have been utilized for EV-based delivery of oncolytic viruses (OVs). For example, OV-encapsulated EVs from liver cancer cells or erythrocytes were injected into mice bearing subcutaneous liver tumors 61. Treatment with OV-loaded EVs led to improved tumor growth inhibition compared to treatment with OVs, indicating that EVs shielded the viruses from immunological recognition and clearance.…”

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

“…Avoiding virus neutralization is achievable by chemical or physical modification with various biomaterials. An example of this strategy is the encapsulation and coating of virion with liposomes [ 156 , 157 ], nanovesicles [ 158 ], or polymers [ 159 ]. Some materials with stimuli-responsive properties may provide superior potential for systemic therapy, such as a pH-sensitive copolymer modified adenovirus for targeting the acidic tumor environment [ 160 ], and an enzyme-responsive liposome-coated adenovirus for reducing immunogenicity [ 161 ].…”

Nanoparticle Delivery of Immunostimulatory Agents for Cancer Immunotherapy

“…Cancer cell membrane represents a rich source of functional ligands as well as TAAs 115, 116, and these properties have been leveraged in the design of hybrid nanostructures for cancer imaging 211, photothermal therapy 212, photodynamic therapy 213, virotherapy 214, and immunotherapy 215. In one such work on cancer immunotherapy, the immunogenic properties of HSP70 was leveraged to enhance immune responses against cancer cell membrane antigens 216.…”