Abstract Rationale Acute lung injury (ALI) is characterized by excessive inflammatory responses and oxidative stress, leading to rapid disease progression and high mortality. Although probiotics have emerged as promising platforms for localized delivery of therapeutic molecules, their efficacy in ALI remains constrained by limited anti-inflammatory capacity and poor retention at inflamed sites. Objective We developed a dual-functional engineered Lactobacillus paracasei capable of both cytokine delivery and microenvironment-responsive antioxidation. Methods Using synthetic biology, L. paracasei was engineered to secrete the anti-inflammatory cytokine IL-4. Subsequently, a material-based surface modification strategy was applied to endow the strain with targeted accumulation in inflamed lung tissue and efficient clearance of reactive oxygen species (ROS). Results In vitro experiments demonstrated that the engineered strain markedly suppressed the production of pro-inflammatory cytokines (TNF-α and IL-6) while reducing intracellular ROS levels. In LPS- and Pseudomonas aeruginosa-induced ALI mouse models, treatment with the engineered bacteria effectively alleviated pulmonary inflammation, improved histopathological damage, and reduced the lung wet/dry weight ratio, with therapeutic efficacy increasing over time. Moreover, metabolomic profiling revealed that the intervention remodeled the pulmonary microenvironment, notably increasing host-beneficial metabolites such as indole-3-butyric acid. Conclusion This study establishes a synergistic probiotic strategy that integrates synthetic biology and responsive materials engineering to achieve targeted delivery, immune modulation, and ROS scavenging. The engineered probiotic exhibits robust therapeutic efficacy in ALI and provides a versatile platform for treating inflammation-related respiratory diseases. This abstract is funded by: None
Qian et al. (Fri,) studied this question.