Inhaled nanogels ameliorate vascular remodeling in pulmonary arterial hypertension via normalization of endothelia-smooth muscle cell crosstalk

Maintaining appropriate vascular nitric oxide (NO) levels in pulmonary arteries is crucial for the alleviation of pulmonary arterial hypertension (PAH). However, in the injured vascular microenvironment, excessive reactive oxygen species (ROS) deplete NO to generate peroxynitrite, which aggravates the oxidative stress and endothelial dysfunction. Herein, ROS-responsive, zwitterionic nanogels (NGs), containing arginine pendants as NO precursors and encapsulating resveratrol (RSV) as an anti-oxidant, were developed for PAH management via inhalation. Benefiting from their zwitterionic surface that repels mucin adsorption, the inhaled NGs exhibit effective pulmonary mucus penetration and mucosal absorption, enabling robust diffusion to the injured pulmonary arteries. In the oxidative vascular microenvironment, the diselenide crosslinkers within the NGs are cleaved, promoting NGs dissociation and on-demand RSV release. The released RSV scavenges ROS and the arginine pendants are oxidized to generate NO, which cooperate to interrupt the ROS/NO disequilibrium. In a hypoxia/SU5416-induced PAH mouse model, inhaled NGs efficiently alleviate vascular remodeling and reduce pulmonary arterial pressure. This study offers an effective strategy for pulmonary drug delivery, and holds promising potentials for the management of PAH.