Probiotic domestication and engineering enable one-shot treatment for bladder mucosal repair.

Abstract

The bladder mucosa is an important blood-urine barrier in the human body, its destruction can lead to distressing cystitis. Traditional treatment approaches often require frequent catheterization and intravesical instillation of hyaluronic acid (HA), which greatly reduces patient compliance and therapeutic efficacy. Herein, we develop a probiotic-based one-shot therapy to repair bladder mucosa with improved convenience, efficacy, and biosafety. To this end, a high-biocompatible probiotic strain is engineered to secrete high-molecular-weight HA controlled by ultrasound stimulation. Meanwhile, a bacterium acclimation-inspired strategy to select bacterial cells targeting the site of bladder inflammation is also proposed. With just one-shot intravesical administration, these engineered bacteria can strongly adhere to the damaged bladder epithelium, continuously secrete HA, and stimulate the formation of protective living engineered materials on the bladder. Consequently, varying therapeutic efficacies in damaged murine model, such as reporting the site of inflammation within 28 days, accelerating mucosal repair (such as significantly increased expression of tight junction proteins occludin-1 and ZO-1), modulating innate immune reactions (such as pro-inflammatory factor levels decreased by about 50 %), and even recovering animal motion behaviors, are realized, achieving an improved therapeutic effect without detectable adverse effects.