BacStar · Design, Build and Test of novel bacteria-delivered proteins for cancer therapy

Design, Build and Test of novel bacteria-delivered proteins for cancer therapy

Context and Overall Objectives BacStar sits at the intersection of cancer therapy, synthetic biology, and computational protein design. While bacterial-based cancer therapies show promise—especially engineered strains that colonise tumours and produce therapeutic proteins in situ—a key limitation remains: getting those proteins efficiently into cancer cells. Most current strategies rely on invasive strains or protein modifications like cell-penetrating peptides, both of which face safety, efficiency, and compatibility issues. BacStar aims to solve this delivery bottleneck. The project’s goal is to develop a modular, safe, and robust platform to deliver de novo designed therapeutic proteins directly into the cytoplasm of cancer cells using engineered non-invasive bacteria. Originally, I proposed self-delivering proteins capable of crossing membranes autonomously. However, early in the project, a major advance by Kreitz et al. [9]—the demonstration of programmable protein delivery using bacterial Contractile Injection Systems (CIS)—led to a strategic shift. CIS technology offers a more direct and versatile solution for intracellular protein delivery, better aligning with BacStar’s objectives. To achieve this, the project pursues four objectives: • Design potent protein/peptide therapeutics candidates (e.g. mini-binders, macrocyclic peptides) using state-of-the-art computational tools (e.g. RFDiffusion, MPNN) and validate targeting cancer-relevant intracellular proteins (e.g. Trim21, MCL1, MDM2, GABARAP). • Engineer bacterial strains with functional CIS machinery to deliver these payloads intracellularly. • Create tools (e.g. imaging binders) that facilitate the monitoring of these bacterial deliveries. Scale and significance of the project’s expected impacts: Intracellular delivery is a major limitation for the development of biotherapeutics (e.g. proteins) known to have higher interaction accuracy, binding efficiency, and thus have the potential of acting more effectively than small molecules. Using live bacterial systems could be transformative. This project’s integrated synthetic biology, computational design, and bacterial engineering to bring forward a novel therapeutic platform with broad application in oncology and multiple other diseases, and in applications beyond health, for example in agriculture, forestry, biodiversity conservation and pest control. Scientific Impact: BacStar proposes a new paradigm in live bacterial therapeutics by linking AI-based protein design with precision intracellular delivery. It will provide an open-source platform, validated CIS system, and new therapeutic candidates—enabling progress against targets previously considered undraggable. Societal Impact: By enabling targeted delivery of potent protein drugs, BacStar supports the EU Cancer Mission and UN SDGs. The approach may offer more effective, less toxic therapies and could extend to vaccines or treatments for other diseases. Economic Impact: The project is expected to generate IP on therapeutic designs and delivery tools, with commercial potential through biotech spin-outs or partnerships. This contributes to Europe’s leadership in synthetic biology and strengthens its bioeconomy.

Data: CORDIS, © European Union