Biotrauma characterized by the release of inflammatory cytokines is a key pathological basis of ventilator-induced lung injury (VILI). Small interfering RNA (siRNA) can effectively reduce the release of inflammatory cytokines by inhibiting corresponding inflammatory pathways but may also affect innate immune responses. Therefore, it is promising to target ventilation-induced cytokine production without impairing lung innate immunity. We developed a novel approach to identify peptide targeting activated alveolar epithelial cells (AECs) in VILI mice by incorporating phage display, high-throughput sequencing, and bioinformatics analysis, and identified a pentapeptide (SPFPT) with high affinity for activated AECs. The SPFPT peptide was then conjugated into lipid nanoparticles (LNPs) to co-deliver importin-7 siRNA (siImp7) and polydatin (PD). The delivery efficiency and biological activity of SPFPT@siImp7/PD-LNP were assessed by and experiments. SPFPT@siImp7/PD-LNP demonstrated significant enhancement in targeting mechanical stretch-activated AECs both and . Intratracheal administration of SPFPT@siImp7/PD-LNP effectively inhibited the release of inflammatory cytokines and ameliorated VILI and associated distal organ injury by simultaneously suppressing p38 and NF-κB pathways. Importantly, SPFPT@siImp7/PD-LNP did not interfere with lung innate immunity. The results suggest that the nanocomplex of SPFPT@siImp7/PD-LNP is promising to be highly effective in the precise treatment of VILI.