Ciliotherapy: Remote Control of Primary Cilia Movement and Function by Magnetic Nanoparticles

Patients with polycystic kidney disease (PKD) are characterized with uncontrolled hypertension. Hypertension in PKD is a ciliopathy, an abnormal function and/or structure of primary cilia. Primary cilia are cellular organelles with chemo and mechanosensory roles. In the present studies, we designed a cilia-targeted (CT) delivery system to deliver fenoldopam specifically to the primary cilia. We devised the iron oxide nanoparticle (NP)-based technology for ciliotherapy. Live imaging confirmed that the CT-Fe₂O₃-NPs specifically targeted primary cilia in cultured cells in vitro and vascular endothelia in vivo. Importantly, the CT-Fe₂O₃-NPs enabled the remote control of the movement and function of a cilium with an external magnetic field, making the nonmotile cilium exhibit passive movement. The ciliopathic hearts displayed hypertrophy with compromised functions in left ventricle pressure, stroke volume, ejection fraction, and overall cardiac output because of prolonged hypertension. The CT-Fe₂O₃-NPs significantly improved cardiac function in the ciliopathic hypertensive models, in which the hearts also exhibited arrhythmia, which was corrected with the CT-Fe₂O₃-NPs. Intraciliary and cytosolic Ca²⁺ were increased when cilia were induced with fluid flow or magnetic field, and this served as a cilia-dependent mechanism of the CT-Fe₂O₃-NPs. Fenoldopam-alone caused an immediate decrease in blood pressure, followed by reflex tachycardia. Pharmacological delivery profiles confirmed that the CT-Fe₂O₃-NPs were a superior delivery system for targeting cilia more specifically, efficiently, and effectively than fenoldopam-alone. The CT-Fe₂O₃-NPs altered the mechanical properties of nonmotile cilia, and these nano-biomaterials had enormous clinical potential for ciliotherapy. Our studies further indicated that ciliotherapy provides a possibility toward personalized medicine in ciliopathy patients.