Pro‐Peptide‐Reinforced, Mucus‐Penetrating Pulmonary siRNA Delivery Mitigates Cytokine Storm in Pneumonia

Abstract Pulmonary delivery of anti‐inflammatory siRNA holds great potential in mitigating the cytokine storm during severe pneumonia. However, commonly utilized polycationic siRNA delivery vehicles can hardly penetrate the mucus barrier, thus greatly hurdling their therapeutic efficacy. Herein, TNF‐α siRNA (siTNF‐α) delivery nanocomplexes (NCs) are engineered with mucus/cytomembrane dual‐penetration capabilities, realized via surface‐coating of NCs with RC, an inflammation‐sheddable, charge‐reversal pro‐peptide of RAGE‐binding peptide (RBP). RC‐coated dendritic poly‐_L‐lysine/siTNF‐α (DsT) NCs possess negative surface charges, and can thus efficiently penetrate the mucus layer after intratracheal administration. In the inflamed alveolar space with mild acidity, RC recovers to the cationic RBP and shed off, re‐exposing the DsT NCs that efficiently transfect the alveolar macrophages and provokes TNF‐α silencing. Thus, siTNF‐α and RBP cooperatively alleviate the uncontrolled inflammation during acute lung injury. This study renders a unique approach for mediating trans‐mucus nucleic acid delivery, and will find promising utilities for the treatment of severe pneumonia.