Abstract Acute lung injury (ALI) is a frequent and serious complication of sepsis with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis‐associated ALI can help develop new therapeutic strategies. Herein, the crucial role of cell‐free mitochondrial DNA (cf‐mtDNA) in the regulation of alveolar macrophage activation during sepsis‐associated ALI is identified. Most importantly, a biocompatible hybrid protein nanomotor (NM) composed of recombinant deoxyribonuclease I (DNase‐I) and human serum albumin (HSA) via glutaraldehyde‐mediated crosslinking is prepared to obtain an inhalable nanotherapeutic platform targeting pulmonary cf‐mtDNA clearance. The synthesized DNase‐I/HSA NMs are endowed with self‐propulsive capability and demonstrate superior performances in stability, DNA hydrolysis, and biosafety. Pulmonary delivery of DNase‐I/HSA NMs effectively eliminates cf‐mtDNAs in the lungs, and also improves sepsis survival by attenuating pulmonary inflammation and lung injury. Therefore, pulmonary cf‐mtDNA clearance strategy using DNase‐I/HSA NMs is considered to be an attractive approach for sepsis‐associated ALI.
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