Nanocarrier-based drug delivery strategies for Raynaud's phenomenon: Overcoming microvascular and perfusion barriers

Raynaud's phenomenon (RP) is a functional vascular disorder characterized by episodic vasospasm of the digital microcirculation, resulting in transient ischemia, sensory disturbances, and pain. Despite long-standing clinical recognition, effective pharmacological management of RP remains challenging due to perfusion-limited drug delivery, short drug residence time at ischemic sites, and frequent systemic adverse effects associated with conventional vasodilator therapies. These limitations are particularly pronounced in secondary RP, where structural microvasculature damage further compromises therapeutic efficacy. Emerging nanocarrier-based drug delivery systems offer a promising strategy to address these challenges by enhancing drug stability, improving site-specific accumulation, and enabling controlled or stimuli-responsive release in affected tissues. This review examines RP from a drug-delivery-oriented perspective, highlighting how nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, micelles, and nanoemulsions can overcome RP-specific vascular and cutaneous barriers. Particular emphasis is placed on aligning nanocarrier design with RP pathophysiology, including episodic ischemia, endothelial dysfunction, oxidative stress, and differences between primary and secondary disease. Route-specific delivery strategies and translational considerations, including manufacturing and regulatory challenges, are also discussed. By reframing RP as a delivery-limited disorder rather than solely a pharmacological one, this review provides a translational framework for the rational development of next-generation, personalized nanomedicine-based therapies for RP.