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 surfacecoating of NCs with RC, an inflammation-sheddable, charge-reversal pro-peptide of RAGE-binding peptide (RBP). RC-coated dendritic poly-Llysine/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.

Phosphorus dendron nanomicelles as a platform for combination anti-inflammatory and antioxidative therapy of acute lung injury

“…Because systemically administrated NPs exhibit inevitable side effects in major organs and low accumulation in lung lesion, here we used an in-situ bronchial atomization administration to treat ALI mice. Since the wet/dry weight ratio of lung is one important indicator of the severity of ALI 41 , 42 , we first checked this after different treatments. Among all treatment groups ( Figure S20 ), the wet/dry weight ratio of lung tissues is the highest in the LPS-treated positive control group, and decreases after treatments with C11G3-TBP, free Cur or C11G3-TBP@Cur.…”

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

“…Also, positively charged particles will be more trapped in the mucus rich in anionic mucin glycoproteins than the negatively charged particles. Yet, the commonly utilized siRNA delivery vehicles are polycationic which may hurdle their penetration to the mucus barrier, and therefore their therapeutic efficacy 80 . In contrast, neutral particles exhibited higher average transport rates 75 .…”

“…In addition to the glycosylated regions, the mucin peptides may also trap hydrophobic particulates ( Fig. 4 ) 72 , 78 , 79 , 80 , 81 . Favorably, an enhanced mucoadhesion could prolong the lung retention time of pulmonary delivered particles, leading to an improved and pharmacokinetic profile 75 .…”

“…Poly-L-lysine (PLL) is a well-known cationic polymer that has been widely studied as a non-viral gene delivery vector owing to its strong positive charge 74 . Recently, Yang J et al 80 used dendritic PLL to deliver TNF- α siRNA to the lung. Interestingly, they have used charge-reversible pro-peptide of RAGE-binding peptide modified with cis-aconitic anhydride for the surface-coating of the delivery nanocomplex and giving it a negative surface charge.…”

“…This allowed an efficient mucosal penetration of the developed nanosystem after intratracheal delivery. Then, the positive charge was recovered in the mild acidity of the inflamed alveolar space (pH ≈6.8), allowing efficient transfection of AMs and TNF- α silencing 80 .…”