Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases

Abstract

Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors.

An Engineered Bacteria-Hybrid Microrobot with the Magnetothermal Bioswitch for Remotely Collective Perception and Imaging-Guided Cancer Treatment

“…The results indicated that the good anchoring ability and penetration properties of microrobots (Figure d). It should be noted that bacteria invasion to cells is closely associated with flagella, which sense the cell surface and determine the optimal location for invasion. − We then tested the ROS level in CT26 cells cocultured with the microrobots under the AMF. Figure e showed that the EcN@MNP + MH group significantly elevated the intracellular ROS level as compared to the MNP + MH group.…”

Salmonella as a Promising Curative Tool against Cancer

“…Recently, protein drug delivery to tumors was demonstrated by Raman et al The group used intracellular delivery of Salmonella to express constitutive two-chain active caspase-3, an engineered form of caspase-3 that causes apoptotic cell death. They developed the strain by engineering genetic circuits to enable autonomous deposition of protein payloads directly into cancer cells that decreased tumor growth and reduced breast metastases [ 48 ]. Transforming growth factor alpha (TGFα) is a natural ligand for epidermal growth factor receptor (EGFR), a receptor highly expressed in tumor cells [ 49 ].…”

Coating bacteria for anti-tumor therapy

“…The drug-carrying microcells showed significant inhibition on the growth of breast cancer without any significant toxicity. Raman et al (2021) developed a Salmonella vector with controlled drug synthesis and cellular invasion and achieved effectively reduced tumor growth and metastasis. Salmonella -based protein delivery shows a safe and effective treatment for tumors to provide new therapy for untreatable cancers.…”