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

Abstract

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.

Potential roles of hyaluronic acid in in vivo CAR T cell reprogramming for cancer immunotherapy

“…Minimizing the positively charged complexes dramatically decreases cytotoxicity [39][40][41], immunogenicity [42], and prevents coagulation with serum proteins [43][44][45], avoiding complement activation and a rapid clearance from the systemic circulation. In addition, anionic shielding improves penetration through the layer of negatively charged glycoproteins, such as mucin, to the target tissues [46]. The most common polycation for polyplex formation is polyethyleneimine (PEI), a polymer containing amine groups that can be protonated at a wide range of pH, allowing electrostatic interaction with phosphate groups of DNA or RNA [9] and facilitating endosomal escape from the proton sponge effect [47].…”

“…In addition, anionic shielding improves penetration through the layer of negatively charged glycoproteins, such as mucin, to the target tissues. 46 The most common polycation for polyplex formation is polyethyleneimine (PEI), a polymer containing amine groups that can be protonated over a wide range of pH, allowing electrostatic interaction with the phosphate groups of DNA or RNA 9 and facilitating endosomal escape from the proton sponge effect. 47 However, due to the inherent cytotoxicity and non-biodegradability of PEI, chitosan, a naturally derived cationic polysaccharide with biodegradability and biocompatibility profiles, offers a safer alternative to use with HA in the formation of gene complexes.…”

“…In addition, anionic shielding improves penetration through the layer of negatively charged glycoproteins, such as mucin, to the target tissues. 46 The most common polycation for polyplex formation is polyethyleneimine (PEI), a polymer containing amine groups that can be protonated over a wide range of pH, allowing electrostatic interaction with the phosphate groups of DNA or RNA 9 and facilitating endosomal escape from the proton sponge effect. 47…”

Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage

“…The main pathogenesis of ALI are sharp increase in pulmonary inflammatory responses, diffused alveolar injury and pulmonary edema, which might ultimately lead to acute hypoxemia (2). Currently, the clinical treatment for ALI is limited and specific drugs for ALI are also still lacking (3). Even though mechanical ventilation could partially relieve the pathology of ALI, long-term mechanical ventilation always increases ventilator-related lung injury, higher mortality and heavy financial burden (4,5).…”

Nanoscale Porphyrin Metal-Organic Frameworks Deliver siRNA for Alleviating Early Pulmonary Fibrosis in Acute Lung Injury

“…The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy ( Kandil and Merkel 2019 ; Zoulikha et al, 2022 ). For example, inhaled siRNAs can directly target and have long-term contact with pulmonary cells, which can be quickly effective and avoid first-pass elimination ( Merckx et al, 2018 ; Zhu et al, 2022 ). However, large molecular weight (∼14 kDa), abundant negative charge, and poor stability of naked siRNAs limit their permeation across cell membranes ( Wittrup and Lieberman 2015 ; Saeed et al, 2021 ).…”