pH Sensitive Erythrocyte-Derived Membrane for Acute Systemic Retention and Increased Infectivity of Coated Oncolytic Vaccinia Virus

Abstract

Oncolytic viruses have emerged as a promising modality in cancer treatment given their high synergy with highly efficient immune checkpoint inhibitors. However, their potency is limited by their rapid in vivo clearance. To overcome this, we coated oncolytic vaccinia viruses (oVV) with erythrocyte-derived membranes (EDMs), hypothesizing that they would not only remain in systemic circulation for longer as erythrocytes would when administered intravenously, but also respond to environmental pH cues due to their membrane surface sialic acid residues. For this, we developed a model based on DLVO theory to show that the acidic moieties on the surface of EDM confers it the ability to respond to pH-based stimuli. We corroborate our modeling results through in vitro cell culture models and show that EDM-coated oVV infects cancer cells faster under acidic conditions akin to the tumor microenvironment. When EDM-coated oVVs were intravenously injected into wild-type mice, they exhibited prolonged circulation at higher concentrations when compared to the unprocessed oVV. Furthermore, when EDM-coated oVV was directly injected into xenografted tumors, we observed that they were suppressed earlier than the tumors that received regular oVV, suggesting that the EDM coating does not hinder oVV infectivity. Overall, we found that EDM was able to serve as a multi-functional encapsulant that allowed the payload to remain in circulation at higher concentrations when administered intravenously while simultaneously exhibiting pH-responsive properties.

Emerging delivery strategy for oncolytic virotherapy

“…These delivery platforms, through intravenous injection, effectively protected OVs from rapid clearance, thereby significantly enhancing tumor targeting. 66 Moreover, researchers have introduced hybrid membrane vesicles, combining artificial lipid membranes and RBC membranes, for improved surface antigen masking and extended OVs circulation time. 67 …”

Living virus‐based nanohybrids for biomedical applications

“…Liposomes also have been used to camouflage viruses using a thin‐film hydration method, significantly reducing their intrinsic viral immunogenicity (Wang, Huang, et al, 2019). Other natural cell membranes such as red blood cell (RBC) membranes, platelet membranes, and cancer cell membranes have also been utilized for this purpose (Samoranos et al, 2022). Nevertheless, some new discoveries reported by Huang et al demonstrated for the first time that the natural cell membrane alone is not sufficient in preventing antibodies from inactivating the virus due to their high permeability (Huang, Sun, et al, 2022).…”

Joining Forces: The Combined Application of Therapeutic Viruses and Nanomaterials in Cancer Therapy

“…For example, treatment with trichostatin A (TSA) for oral squamous cell carcinoma (SCC) can activate nuclear factor-kappa B (NF-kB), thereby enhancing the replication of gamma(1) 34.5-deficient oncolytic HSV-1 (oHSV) [81]. iRGD tumor-penetrating peptide-modified OAds have shown enhanced tumor transduction, intratumoral spread, and anti-tumor effects [82] Lastly, oncolytic vaccinia virus (OVV) coated with erythrocyte-derived membranes (EDM) is expected not only to circulate longer in vivo, similar to intravenously injected erythrocytes, but also to respond to environmental pH changes, due to their unique properties [83].…”