Macrophage membrane-coated NIR light-photodegradable carbon nitride-based gene vectors for gas-gene therapy of liver fibrosis

Hepatic fibrosis impacts millions of patients globally suffering from various liver diseases. Therefore, development of novel therapeutic strategies is urgently required. Since macrophage recruitment increases during liver fibrosis progression, macrophage membrane-coated biomimetic complexes can be designed for targeted anti-liver fibrosis therapy. In this study, a biomimetic “gas-gene” strategy was proposed to enhance anti-liver fibrosis efficacy. A macrophage membrane-coated carbon nitride-based biomimetic delivery platform loaded with DNA nanoparticles (M-PEISeCCNs@DNA) was developed. The macrophage membrane coating facilitated the delivery of M-PEISeCCNs@SBP1 to the liver fibrosis site and reversed the positive charge of the carriers to avoid cation-induced cytotoxicity. Under near-infrared (NIR) irradiation, M-PEISeCCNs@SBP1 could trigger water splitting to produce O₂, thereby mitigating hypoxia and alleviating liver fibrosis. The light-responsive release of the SBP1-DNA plasmid was also achieved through carrier photolysis. The delivered SBP1-DNA and the Se element within the vectors synergistically upregulated the expression of selenium-binding protein-1 (SBP1). Additionally, we demonstrated for the first time that SBP1 is an effective therapeutic target for liver fibrosis, and its overexpression inhibits epithelial-mesenchymal transition (EMT) and attenuates CCl₄-induced liver fibrosis in mice. In this experiment, M-PEISeCCNs@SBP1 effectively treated liver fibrosis in mice through the SBP1-mediated NOTCH2/Wnt pathway.