Researchers from Columbia University have developed a platform called CAPPSID (Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery) that leverages engineered Salmonella typhimurium bacteria to deliver and control an oncolytic virus inside tumors.
Both bacteria and viruses have been explored as medicines against cancer. Oncolytic viruses selectively infect and destroy cancer cells, while bacteria can be engineered to home in on tumors and deliver therapeutic payloads. Yet each approach faces limitations. Oncolytic viruses often struggle to reach tumors after systemic administration because pre-existing antiviral antibodies neutralize them before they arrive. Engineered bacteria such as attenuated Salmonella can colonize tumors and deliver genetic material, but they typically remain confined to the tumor core, limiting their reach and therapeutic effect. The CAPPSID system was designed to overcome these obstacles by combining the strengths of both microbes.
Essentially, CAPPSID transforms bacteria into a kind of living viral capsid. The engineered S. typhimurium transcribes and releases the genome of Senecavirus A (SVA), an oncolytic picornavirus that can selectively infect and destroy cancer cells, inside tumor cells.
Several innovations make this system possible:
Intracellular sensing and RNA transcription – The bacteria use promoters that activate only once inside mammalian cells to drive the production of viral RNA.
Bacterial self-lysis for delivery – Two lytic proteins disrupt both the bacterial membrane and the vacuole that normally contains the bacteria inside host cells, releasing viral RNA into the cytoplasm.
Controlled viral spread – The team engineered SVA to require a bacterially supplied protease for proper viral maturation. This gives the bacteria control over how far and how long the virus can replicate.
The result is a coordinated bacterial-viral partnership in which the bacteria carry the virus safely past systemic immunity, then release it directly into tumor cells, where the virus can replicate and spread. Notable outcomes in both cell culture and animal models include efficient viral delivery across cell types, in vivo tumor clearance in mice with small-cell lung cancer tumors, and antiviral immunity even in pre-exposed mice.
“This work extends bacterially delivered therapeutics to viral genomes, and shows how a consortium of microbes can achieve a cooperative aim,” write the authors. “By developing a bacterially delivered platform for viral RNA, we show successful launch of a viral infection capable of eradicating tumours, the ability to cloak and deliver viral genomes into tumours in mice with humoral immunity, and that viral spreading controlled in trans by a bacterially donated protease can enhance persistence compared with a replicon alone. Together, this engineered microbial consortium produces a potent therapy that overcomes the limitations of singular approaches.”
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