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 regulatorflhDCto 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 withflhDCincreases 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. 
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                            Cancer Cell Membrane-Coated Nanoparticles for Cancer Management
                        
                    
    
            Cancer is a global health problem in need of transformative treatment solutions for improved patient outcomes. Many conventional treatments prove ineffective and produce undesirable side effects because they are incapable of targeting only cancer cells within tumors and metastases post administration. There is a desperate need for targeted therapies that can maximize treatment success and minimize toxicity. Nanoparticles (NPs) with tunable physicochemical properties have potential to meet the need for high precision cancer therapies. At the forefront of nanomedicine is biomimetic nanotechnology, which hides NPs from the immune system and provides superior targeting capabilities by cloaking NPs in cell-derived membranes. Cancer cell membranes expressing “markers of self” and “self-recognition molecules” can be removed from cancer cells and wrapped around a variety of NPs, providing homotypic targeting and circumventing the challenge of synthetically replicating natural cell surfaces. Compared to unwrapped NPs, cancer cell membrane-wrapped NPs (CCNPs) provide reduced accumulation in healthy tissues and higher accumulation in tumors and metastases. The unique biointerfacing capabilities of CCNPs enable their use as targeted nanovehicles for enhanced drug delivery, localized phototherapy, intensified imaging, or more potent immunotherapy. This review summarizes the state-of-the-art in CCNP technology and provides insight to the path forward for clinical implementation. 
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                            - Award ID(s):
- 1752009
- PAR ID:
- 10139270
- Date Published:
- Journal Name:
- Cancers
- Volume:
- 11
- Issue:
- 12
- ISSN:
- 2072-6694
- Page Range / eLocation ID:
- 1836
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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