Cardiovascular disease remains the world’s leading cause of death, but most current therapies focus on lowering cholesterol rather than directly targeting the inflammation that fuels disease progression. 

A recent study by Northwestern Engineering’s Lisa Volpatti aims to change that paradigm. 

The research reveals a method for precisely targeting inflammation at the site of disease instead of broadly suppressing the immune system to address the issue. By repurposing so-called “bad cholesterol” as a delivery vehicle for anti-inflammatory therapy, the work suggests a potentially safer and more effective way to treat atherosclerosis, the buildup of fatty plaques in artery walls, narrowing them and reducing blood flow. The findings also point to a broadly applicable strategy for improving the delivery of protein-based medicines for other metabolic diseases, including diabetes and liver disease.

Crucially, the work shows that the inflammatory drivers of cardiovascular disease can be targeted with precision rather than treated systemically. The work introduces a new delivery approach that leverages low-density lipoprotein (“bad cholesterol”), a natural component of atherosclerosis, to selectively transport therapeutic proteins to diseased tissue.

Volpatti is an assistant professor of biomedical engineering and chemical and biological engineering in the McCormick School of Engineering. She presented the work in the paper “LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice,” published last month in the academic journal Nature Biomedical Engineering.

This paper builds on a substantial body of evidence showing that Interleukin-10 (IL-10)—an anti-inflammatory cytokine produced by immune cells that suppresses excessive immune responses and helps resolve inflammation—can be effective in treating atherosclerosis by modulating inflammatory pathways, as demonstrated in genetic mouse models and related studies. Despite its well-established biological importance, efforts to translate IL-10 into a viable therapy have been hampered by delivery challenges and off-target effects.

This study addresses that central limitation by introducing a targeted delivery strategy that directs IL-10 to atherosclerotic plaques with precision, enabling the therapeutic potential of a molecule long recognized as effective but difficult to apply clinically.

Although anti-inflammatory proteins are highly effective, their clinical use has been constrained by side effects and poor localization to diseased tissue. In the research, Volpatti describes a therapeutic strategy that enables precise delivery of anti-inflammatory proteins to atherosclerotic plaques by engineering them to hitchhike on low-density lipoprotein, the same “bad cholesterol” that accumulates in diseased arteries. In mouse models of atherosclerosis, this targeted approach concentrated the therapy in plaques, reduced immune cell infiltration to levels seen in healthy animals, and suppressed inflammatory activity in plaque-associated macrophages.

“Because this platform is modular, it could be broadly applied to improve the safety and effectiveness of biologic therapeutics for atherosclerosis and other metabolic diseases,” Volpatti said.

Next steps include clarifying the therapy’s mechanism of action, further enhancing its potency and circulating half-life, and extending the approach to additional disease models. Ongoing work at Northwestern is focused on refining the delivery platform and evaluating its broader applicability for treating inflammatory diseases beyond atherosclerosis.