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Targeted Thrombolysis via CCR2-Engineered Macrophage-Mimicking Microbubbles Safely Ablates Venous, Arterial, and
Buying Li1, Changjin Lu2, Shijie Gao1
1Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China.
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.
Insights
Researchers developed smart microbubbles that target inflammation to precisely dissolve blood clots. This novel approach enhances thrombolysis, offering a safer and more effective treatment for thrombotic diseases.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Pharmacology
Background:
- Thrombosis is a leading cause of mortality globally.
- Current thrombolytic therapies have limitations, including short half-life and bleeding risks.
Purpose of the Study:
- To design and validate an intelligent, inflammation-targeting microbubble for precise thrombolysis.
- To develop a biomimetic system for targeted drug delivery to thrombotic sites.
Main Methods:
- Engineered macrophages to overexpress C-C chemokine receptor 2 (CCR2).
- Functionalized liposomal microbubbles with macrophage membranes, co-encapsulating urokinase (UK) and perfluoropropane gas (UK@CCR2/MBs).
- Utilized ultrasound to trigger drug release upon targeting monocyte chemoattractant protein-1 (MCP-1) at thrombotic sites.
Main Results:
- UK@CCR2/MBs demonstrated superior thrombolytic efficacy in vitro and in vivo models (deep vein, carotid artery, microcirculatory thrombosis).
- Achieved specific targeting of thrombotic sites with an excellent safety profile.
- Confirmed ultrasound-responsive drug release and macrophage-mimicking homing capabilities.
Conclusions:
- Macrophage-mimicking, ultrasound-responsive microbubbles offer a sophisticated theranostic platform.
- This system enables non-invasive and targeted treatment of thrombotic diseases.
- The approach overcomes limitations of conventional thrombolytic agents.
