Neutrophil membrane-coated nanoparticles for targeted delivery of toll-like receptor 4 siRNA ameliorate LPS-induced acute lung injury

Pulmonary delivery of small interfering RNAs (siRNAs) is an effective treatment for acute lung injury (ALI), which can modulate the expression of pro-inflammatory cytokines and alleviate the symptoms of ALI. However, the rapid degradation of siRNA in vivo and its limited ability to target and validate cells are important challenges it faces in clinical practice. In this work, we developed neutrophil membrane-coated Poly (lactic-co-glycolic acid) nanoparticles loaded with TLR4 siRNA (si-TLR4) (Neutrophil-NP-TLR4), which can target both inflammatory and macrophage cells to alleviate the pulmonary inflammation in lipopolysaccharide (LPS)-induced ALI mice. These Neutrophil-NP-TLR4 effectively reduce the TNF-alpha and IL-1 beta expressions both in vitro and in vivo. Meanwhile, they also reduced the expression of TLR4, and its downstream genes including TNF receptor-associated factor 6 (TRAF6), X-linked inhibitor of apoptosis protein (XIAP), and Nuclear Factor kappa-B (NF-kappa B), but elevated the levels of Aquaporin 1 (AQP1) and Aquaporin 5 (AQP5). Moreover, the Neutrophil-NP-TLR4 precisely targets the inflammatory site to attenuate the lung injury without causing toxicity to normal tissue. This system provides a promising approach to effective delivery of siRNA to precisely treat the ALI.