Abstract

Acute lung injury (ALI) features uncontrolled inflammation and oxidative stress that drive rapid deterioration and high mortality. While probiotics offer a promising vehicle for localized therapeutic delivery, their application in ALI is hindered by limited immunomodulatory activity and insufficient retention within inflamed lung tissue. Here, we report a dual-functional engineered Lactobacillus paracasei that couples cytokine-based immune regulation with microenvironment-responsive antioxidation. Through synthetic biology, the strain was programmed to secrete interleukin-4 (IL-4). A subsequent material-assisted surface modification enhanced the bacterium's ROS scavenging capability and facilitated improved therapeutic effects in inflamed lung tissue. In vitro, the engineered strain markedly suppressed TNF-α and IL-6 production and reduced intracellular ROS. In LPS- and Pseudomonas aeruginosa - induced ALI mouse models, treatment significantly attenuated lung inflammation, alleviated histopathological injury, and decreased the lung wet/dry ratio, with therapeutic benefits accumulating over time. Metabolomic profiling further revealed that the intervention reshaped the pulmonary microenvironment, notably elevating host-beneficial metabolites such as indole-3-butyric acid. Collectively, this work establishes a synergistic probiotic strategy integrating synthetic biology and responsive materials engineering to achieve targeted delivery, immune modulation, and oxidative stress relief. The engineered probiotic demonstrates potent therapeutic efficacy in ALI and represents a versatile platform for managing inflammation-associated respiratory diseases.