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

Area of Science:

• Synthetic biology
• Bacterial cancer therapy
• Pharmacokinetics

Background:

• Synthetic biology advances enable novel bacterial cancer therapies.
• Controlling bacterial behavior in vivo is crucial for therapeutic efficacy and safety.
• Existing pharmacokinetic models struggle to capture the dynamics of living therapeutics.

Purpose of the Study:

• To engineer biosensor-driven encapsulation systems for autonomous control of capsular polysaccharides in *Escherichia coli* Nissle 1917.
• To improve the pharmacokinetic profiles and safety of systemically delivered bacterial therapeutics.
• To develop a two-state pharmacokinetic model for simulating autonomous control of living therapeutics.

Main Methods:

• Constructed biosensor-driven encapsulation systems in *Escherichia coli* Nissle 1917.
• Programmed bacteria for immune evasion via capsular polysaccharide expression and subsequent gene silencing.
• Developed and utilized a two-state pharmacokinetic model to simulate bacterial biodistribution and control.
• Validated the system in a humanized pharmacokinetic model with enhanced complement-mediated lysis.

Main Results:

• Engineered bacteria achieved tumor colonization with controlled capsular polysaccharide expression.
• The two-state pharmacokinetic model accurately simulated bacterial behavior in different compartments.
• Biosensor-driven systems demonstrated comparable tumor seeding to wild-type bacteria.
• Systemic bacterial loads in blood and liver were significantly reduced, enhancing safety.

Conclusions:

• Biosensor-driven systems offer superior autonomous control of bacterial therapeutics compared to inducible systems.
• The developed pharmacokinetic model aids in understanding and optimizing living therapeutics for clinical translation.
• This strategy holds significant potential for safe and effective systemic delivery of bacterial cancer therapies.