Active Anchoring Stimuli‐responsive Nano‐craft to relieve Pulmonary Vasoconstriction by Targeting Smooth Muscle Cell for Hypoxic Pulmonary Hypertension Treatment

Abstract Recently, nanotechnology‐based drug delivery platforms in treating pulmonary arterial hypertension (PAH) have gradually emerged. However, large mechanical stress and shear stress in blood vessels greatly affect the retention of nanopreparative materials at lesion sites, severely limiting nanotechnology‐based drug delivery. Herein, a stimuli‐responsive nanocraft was rationally designed by actively anchoring E‐selectin overexpressed on pulmonary arterial endothelial cells (PAECs), under hypoxic conditions, allowing effective accumulation and retention of the drug at the lesion site. Briefly, we incorporated a nitrobenzene group into the framework of a nanocarrier and simultaneously linked it with chitosan. Additionally, we modified the surface of the nanocarrier with sialic acid (SA) and encapsulated the clinically used drug ambrisentan (Am), which enabled the anchoring of E‐selectin and subsequent drug delivery. This system facilitates intercellular transport to pulmonary artery smooth muscle cells (PASMCs) when targeting PAECs and specifically responds to a reductive hypoxic microenvironment with elevated nitroreductase in PASMCs. Moreover, compared with free Am, nanoencapsulation and SA‐PEG 2000 ‐NH 2 prolonged the blood circulation time, achieving better therapeutic outcomes in preventing vascular remodeling and reversing systolic dysfunction. The originality and contribution of our work reveal the promising value of this pulmonary arterial anchoring stimuli‐responsive nanocraft as a novel therapeutic strategy for satisfactory PAH treatment. This article is protected by copyright. All rights reserved