Pillar arene Se nanozyme therapeutic systems with dual drive power effectively penetrated mucus layer combined therapy acute lung injury

siRNA has demonstrated a promising paradigm for therapy of acute lung injury(ALI). However, the pulmonary mucus layer barrier powerfully hinders the therapeutic efficacy. Herein, we proposed to use dual drive power to enhance the mucus permeation of siRNA by constructing the neutral and targeted selenium nanozymes therapeutic system. The multifunctional selenium nanozymes (CWP–Se@Man) were synthesized by modifying with cationic water-soluble pillar arene (CWP) and mannose (Man). After loading CCR2-siRNA, the CWP-Se@Man reached electroneutrality that co-driven by electroneutrality and targeting, the mucus permeation capacity of CWP-Se@Man enhanced by ∼15 fold, thus effectively penetrate pulmonary mucus layer and deliver CCR2-siRNA into macrophages. Moreover, with optimizing the composition of CWP-Se@Man made of CWP (Slutsky, 2013) [5] or CWP (Ichikado et al., 2012) [6], the therapeutic system CWP (Ichikado et al., 2012) [6]-Se@Man showed better biological activities due to smaller size. In inflamed modes, the CWP-Se@Man nanotherapeutic systems loading CCR2-siRNA not only exerted pronounced anti-inflammatory effect through combining inhibit the chemotactic effect and ROS, but also effectively against ALI after blocking the circulatory effect of ROS and inflammatory cytokines. Therefore, this strategy of dual-driving force penetration mucus renders a unique approach for mediating trans-mucus nucleic acid delivery in lungs, and provide a promising treatment for the acute lung injury therapy.