atherosclerosis biomimetic nanoparticle therapy

cardiovascular disease accounted for 19.4 million deaths globally in 2021, more than transportation accidents, COVID-19, and cancer combined, and is projected to keep growing as an economic burden. atherosclerosis, the inflammatory disease underlying much of that toll, forms plaques within the arteries and is often silent: a sample of individuals aged 50 to 64 with no known coronary heart disease found 42.1% already had subclinical coronary atherosclerosis. this project targets the disease at its origin in the endothelium rather than at the plaque.

under laminar shear stress, endothelial cells signal through nitric oxide and express KLF2, a regulator that maintains endothelial function and suppresses proinflammatory molecules such as VCAM-1 and ICAM-1. at branched arteries, disturbed or oscillatory shear stress instead drives reactive oxygen species (ROS) signaling, inhibits ERK5, activates NF-κB, and promotes the inflammatory state in which low-density lipoproteins and macrophages accumulate in the intima to form fatty streaks and, eventually, plaque.

the therapeutic repurposes metformin to promote KLF2 transcription through two mechanisms: an AMPK-dependent pathway (metformin inhibits mitochondrial complex I, activating AMPK, which acts through ERK5 and MEF2 to promote KLF2 transcription) and a SIRT1-related pathway (metformin enhances SIRT1 activity, which promotes MEK5 and MEF2). to reach the disease site rather than act systemically, the metformin is embedded in ROS-responsive nanoparticles coated in a macrophage cell membrane, which both targets atherosclerotic lesions and evades immune clearance. supporting work shows these macrophage-membrane-coated ROS-responsive nanoparticles have good cytocompatibility in vitro, preserve drug activity, and, in atherosclerotic mice, produce the greatest reduction in ROS among the tested formulations.

the proposed rollout was a three-stage initial clinical trial testing safety, delivery, and efficacy on a small scale, with delivery monitored by fluorescence microscopy and efficacy assessed through MRI and PET/CT scans. manufacturing carries several separate costs, including metformin, nanoparticle formation, macrophage cell sourcing and modification, cell culture, storage, and packaging, so the therapy would always cost more than the oral-medication alternative at roughly $200 to $1000 per dose. that premium is weighed against targeted delivery that avoids the gastrointestinal adverse effects seen in 16 to 62% of people who ingest metformin, and against the potential to be life-altering for those living with atherosclerosis.