Bioengineered gut bacterium synthesizing levodopa alleviates motor deficits in models of Parkinson's disease

L-3,4-Dihydroxyphenylalanine (L-DOPA), synthesized from L-tyrosine, is a direct precursor to dopamine. L-DOPA is the gold-standard treatment for Parkinson's disease (PD), given orally alongside decarboxylase inhibitors (e.g., benserazide) to enhance bioavailability. However, its chronic daily pulsatile-like delivery is associated with complications. Herein, we show the construction and in vivo efficacy of a programmable, titratable, genetically engineered E. coli Nissle 1917 system (EcN_L-DOPA) that continuously synthesizes L-DOPA from L-tyrosine for systemic distribution. Oral administration of EcN_L-DOPA with benserazide maintains therapeutic plasma L-DOPA concentrations and increases brain dopamine levels. EcN_L-DOPA improves motor performance and limits depressive-like behaviors without adverse side effects in healthy mice, Parkinsonian mice, and canine models. Simulated physiological models from pharmacokinetic and pharmacodynamic studies in canines demonstrate the translational feasibility of this biotherapeutic system for potential human studies. This work lays the groundwork for EcN_L-DOPA as a continuous, non-invasive microbial drug delivery platform for PD and chronic neurological diseases.