Inflammation and Microbiota Regulation Potentiate Pneumonia Therapy by Biomimetic Bacteria and Macrophage Membrane Nanosystem

While conventional nanosystems can target infected lung tissue, they cannot achieve precise cellular targeting and enhanced therapy by modulating inflammation and microbiota for effective therapy. Here, we designed a nucleus-targeted nanosystem with adenosine triphosphate (ATP) and reactive oxygen species stimuli-response to treat pneumonia coinfected with bacteria and virus that is enhanced through inflammation and microbiota regulation. The nucleus-targeted biomimetic nanosystem was prepared through the combined bacteria-macrophage membrane and loaded hypericin and ATP-responsive dibenzyl oxalate (MMHP) subsequently. The MMHP despoiled the Mg²⁺ of intracellular cytoplasm in bacteria to achieve an effective bactericidal performance. Meanwhile, MMHP can target the cell nucleus and inhibit the H1N1 virus duplication by inhibiting the activity of nucleoprotein. MMHP possessed an immunomodulatory ability to reduce the inflammatory response and activate CD8⁺ T cells for assisted infection elimination. During the mice model, the MMHP effectively treated pneumonia coinfected with <i>Staphylococcus aureus</i> and H1N1 virus. Meanwhile, MMHP mediated the composition of gut microbiota to enhance the pneumonia therapy. Therefore, the dual stimuli-responsive MMHP possessed promising clinical translational potential to therapy infectious pneumonia.