 This study proposes the use of existing drug-controlled gene switches to enable control of virally-encoded trans-gene expression in vaccinia virus, VV, based on colitic virus designs. These switches include systems controlled by the FDA-approved drugs Rappomycin and DoxaCycline, which can be used to control the timing and dosage of trans-gene expression. Additionally, the authors have developed chimeric synthetic promoters that allow for further regulatory layers for VV-encoded synthetic trans-gene networks. These switches can be used to enable inducible expression of fusogenic proteins, dose-controlled delivery of toxic cytokines, and chemical regulation of VV replication. This toolbox provides researchers with the ability to precisely modulate trans-gene circuits in VV-vectored on colitic virus design. This article was authored by Toho Azad, Riza Rizoi, Rabunov-Sengarivelu, and others.