Studying Nanoparticle Shedding to Improve Targeted Therapies

The development and subsequent approval of SARS-CoV-2 mRNA vaccines saved countless lives during the COVID-19 pandemic. The authorization of those treatments also spurred interest in the use of lipid nanoparticles (LNPs)—tiny fat-based bubbles used to deliver mRNA and other substances inside the body (or into cells)—for other applications such as producing cancer-killing T cells.

For more advanced treatments, these LNPs need a targeting ligand—like an address label—to guide them through the bloodstream to the right cells. This label attaches to the particle’s outer coating, but it can sometimes come loose and fall off.

Recent work from Northwestern Engineering’s Lisa Volpatti studied how parts of these nanoparticles can come loose. This work helps researchers better understand how stable ligands are and where they travel in the body, which are key steps toward getting these types of therapies approved.

Volpatti is an assistant professor of biomedical engineering and chemical and biological engineering at the McCormick School of Engineering. She reported her findings in the paper “PEG-Lipid Shedding and Biodistribution Are Shaped by Nanocarrier Morphology and Lipid Chemistry,” published March 23 in the journal Cell Biomaterials. The research was initiated by Ethan Cisneros, a PhD candidate in biomedical engineering in Volpatti’s lab.

Volpatti’s team investigated how the attachment strength of the targeting ligand to the polyethylene glycol lipid (PEG-lipid) influences the distribution and stability of nanoparticles in the body. The study showed that strongly anchored ligands tend to maintain consistent organ targeting across different nanoparticle structures, while weakly anchored ligands can lead to more varied distribution and potential off-target exposure.

By mapping how these detachment behaviors affect nanoparticle fate, the research provides critical insights for designing nanomedicines that are both safe and effective, improving the precision of therapies that rely on LNPs and tiny drug-carrying particles made from synthetic polymers.

“This work shows that shedding occurs in polymeric nanoparticles and that the extent of shedding depends on PEG-lipid chemistry and nanoparticle morphology,” Volpatti said. “By systematically testing PEG-lipids and morphology, we aim to define molecular and structural parameters for improved biomaterials design.”

This work uses both traditional lab techniques and experiments in living systems to measure how nanoparticles shed parts of their coating. By combining these approaches, the research goes beyond methods that rely only on cells or animals, which often have confounding effects.

This is also in line with recent National Institutes of Health efforts to find alternatives to animal testing.

“By coupling non-living and living systems, we also aim to pave the way towards achieving more efficient results,” Cisneros said.

The team’s next steps include studying this shedding behavior in real-world LNP medicines, like COVID vaccine Spikevax and gene-silencing therapy Onpattro, as well as in disease models to better understand how and why it happens. The lab is exploring these questions to develop clear guidelines for designing both LNP and polymer-based nanoparticles and to evaluate how broadly these findings apply.