Design and Modeling of Biosensor-Driven Encapsulation Systems for Systemic Delivery of Bacterial Cancer Therapy

Advances in synthetic biology continue to potentiate bacterial cancer therapy. Here, we constructed biosensor-driven encapsulation systems for autonomous control of capsular polysaccharides of <i><i>Escherichia coli</i></i> Nissle 1917 to improve pharmacokinetic profiles. The engineered bacteria were programmed to express capsular polysaccharides for immune evasion upon intravenous administration to reach tumors and then turn off gene expression upon colonizing the tumors based on quorum-sensing or acid-sensing to prevent dissemination of bacteria into the systemic circulation. Because a classical pharmacokinetic model could not capture the dynamic nature of living therapeutics, a two-state pharmacokinetic model was developed to simulate the autonomous control of capsular polysaccharides in different biological compartments and their impact on biodistribution. Using this model, we identified parameters in gene circuit dynamics and immune clearance that influence tumor colonization and systemic bacterial persistence. In a "humanized" pharmacokinetic model with an increased rate of complement-mediated lysis of bacteria, biosensor-driven systems achieved tumor seeding densities comparable to wild-type bacteria while reducing bacterial loads in blood and liver by several orders of magnitude, highlighting their potential for safe systemic delivery. The biosensor-driven systems represent a more effective strategy to control living drugs than inducible systems, and the two-state pharmacokinetic model is a first step to capture the autonomous nature of this new class of therapeutics for clinical translation.