Targeted Thrombolysis via CCR2-Engineered Macrophage-Mimicking Microbubbles Safely Ablates Venous, Arterial, and Microvascular Thrombosis.

Abstract

The clinical management of thrombosis, a primary cause of death worldwide, is hampered by the limitations of current thrombolytic agents, including short half-life and high risk of off-target bleeding. Here, we report the design and validation of an intelligent, inflammation-targeting microbubble for precise thrombolysis. We first engineered macrophages to overexpress the C─C chemokine receptor 2 (CCR2) via lentiviral transfection. Membranes derived from these cells were then used to functionalize a liposomal structure, co-encapsulating the thrombolytic drug urokinase (UK) and a phase-change perfluoropropane gas. These resulting biomimetic microbubbles (termed UK@CCR2/MBs) were designed to navigate the vasculature and home in on thrombotic sites by binding to the highly expressed monocyte chemoattractant protein-1 (MCP-1) via the CCR2 receptor. Upon arrival at the target, localized low-frequency ultrasound was applied to trigger acoustic droplet vaporization, leading to microbubble disruption and spatiotemporally controlled UK release. Extensive in vitro and in vivo evaluations, including in animal models of deep vein, carotid artery, and microcirculatory thrombosis, confirmed that UK@CCR2/MBs achieve superior thrombolytic efficacy and specific targeting with an excellent safety profile. This macrophage-mimicking, ultrasound-responsive system represents a sophisticated theranostic platform for the non-invasive and targeted treatment of thrombotic diseases.