Surface Coating of Pulmonary siRNA Delivery Vectors Enabling Mucus Penetration, Cell Targeting, and Intracellular Radical Scavenging for Enhanced Acute Lung Injury Therapy

Pulmonary delivery of anti-inflammatory siRNA presents a promising approach for localized therapy of acute lung injury (ALI), while polycationic vectors can be easily trapped by the negatively charged airway mucin glycoproteins and arbitrarily internalized by epithelial cells with nontargetability for immunological clearance. Herein, we report a material, the dopamine (DA)-grafted hyaluronic acid (HA-DA), coating on an anti-TNF-α vector to address these limitations. HA-DA was simply synthesized and facilely coated on poly(β-amino ester) (BP)-based siRNA vectors via electrostatic attraction. The resulting HA-DA/BP/siRNA displayed significantly enhanced mucus penetration, attributable to the charge screen effect of HA-DA and the bioadhesive nature of the grafting DA. After transmucosal delivery, the nanosystem could target diseased macrophages via CD44-mediated internalization and rapidly escape from endo/lysosomes through the proton sponge effect, resulting in effective TNF-α regulation. Meanwhile, DA modification endowed the coating material with robust antioxidative capability to scavenge a broad spectrum of reactive oxygen/nitrogen species (RONS), which protected the lung tissue from oxidative damage and synergized with anti-TNF-α to inhibit a cytokine storm. As a result, a remarkable amelioration of ALI was achieved in a lipopolysaccharide (LPS)-stimulated mice model. This study provides a multifunctional coating material to facilitate pulmonary drug delivery for the treatment of lung diseases.