Genome editing of through targeted delivery of CRISPR-Cas9 system for alleviating acute lung inflammation ERK/NLRP3/IL-1 and NO/iNOS signalling.

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases, immune cell infiltration and protease-driven tissue damages. It is an urgent need to explore potential drug strategies for mitigating lung inflammation. Protease-activated receptor 2 (PAR2) as a vital molecular target principally participates in various inflammatory diseases intracellular signal transduction. However, it has been rarely reported about the role of PAR2 in lung inflammation. This study applied CRISPR-Cas9 system encoding Cas9 and sgRNA () for knockout and fabricated an anionic human serum albumin-based nanoparticles to deliver with superior inflammation-targeting efficiency and stability (TAP). TAP robustly facilitated to enter and transfect inflammatory cells, eliciting precise gene editing of and . Importantly, deficiency by TAP effectively and safely promoted macrophage polarization, suppressed pro-inflammatory cytokine releases and alleviated acute lung inflammation, uncovering a novel value of PAR2. It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP was mainly dependent on ERK-mediated NLRP3/IL-1 and NO/iNOS signalling. Therefore, this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for deficiency in treating inflammatory diseases.