Mucoadhesive, Antibacterial, and Reductive Nanogels as a Mucolytic Agent for Efficient Nebulized Therapy to Combat Allergic Asthma

Asthma is an intractable disease involving the infiltration of inflammatory cells and mucus plugging. Despite small molecular mucolytics having the ability to break the disulfide bonds of mucins, offering a potential way to overcome the airflow obstruction and airway infection, these mucolytics have limited therapeutic effects in vivo. Therefore, in this work, arginine-grafted chitosan (CS-Arg) is ionically cross-linked with tris(2-carboxyethyl)phosphine (TCEP) to obtain nanogels as a mucolytic agent. The positively charged nanogels effectively inhibit the formation of large aggregates of mucin in vitro, probably thanks to the formation of an ionic interaction between CS-Arg and mucin, as well as the breakage of disulfide bonds in mucin by the reductive TCEP. Moreover, the nanogels show good cytocompatibility at concentrations up to 5 mg mL^-1, exhibiting effective inhibitory effects against the proliferation of both Staphylococcus aureus and Escherichia coli at 5 mg mL^-1. After the administration of the nanogels by nebulization into a Balb/c mouse model with allergic asthma, they can efficiently reduce the mucus obstruction in bronchioles and alveoli and relieve airway inflammation. Therefore, these CS-Arg/TCEP nanogels potentially represent a promising mucolytic agent for the efficient treatment of allergic asthma and other muco-obstructive diseases.