The immune system, the body’s defense network against infections and injuries, can sometimes become too active. In these cases, it can produce too many immune mediators, fragments of genetic material or proteins that regulate immune responses.
An excess of these molecules in the bloodstream can cause severe inflammation, sometimes leading to life-threatening medical conditions such as sepsis and acute lung injury. Sepsis is an extreme and life-threatening response to a bacterial, viral or fungal infection. Acute lung injury, on the other hand, occurs when inflammation causes fluid to leak into the lungs, impairing breathing and potentially leading to respiratory failure.
Some biomedical scientists and engineers have been trying to identify promising solutions to remove these excess immune mediators from the bloodstream. Some proposed approaches rely on lysosome-targeting chimeras (LYTACs), molecules that could remove proteins outside or on the surface of cells, directing them to lysosomes (i.e., organelles that dispose of or recycle food particles and other cell waste).
Researchers at Nanyang Technological University recently engineered new LYTACs that could capture target molecules in the bloodstream and direct them toward lysosomes. These new nanoparticles, dubbed SOLIDs (stiffness-oriented lysosome self-sorting nanodegraders), were introduced in a paper published in Nature Nanotechnology.
“Lysosomes are the natural location for protein degradation in cells,” Dr. Jiayan Wu and Prof. Kanyi Pu, first and senior authors of the paper, respectively, told Tech Xplore.
“A technology known as LYTACs captures protein targets and transports them to lysosomes for degradation. However, conventional LYTAC designs rely on a ‘lysosome-sorting moiety’ to target lysosomes, and some lysosome-sorting designs are susceptible to serum interference.”
Pu’s research group at Nanyang Technological University has been designing specialized materials for specific applications for several years. In recent years, the group gained extensive experience in the synthesis of semiconducting polymers (SPs) with characteristic rigid structures (i.e., Ï€-conjugated backbones).
“In our previous studies, we found that SP nanoparticles (SP NPs) with different chemical compositions consistently exhibited preferential lysosomal accumulation without requiring a lysosome-sorting moiety,” said Pu. “This inspired us to explore the potential of SP NPs as lysosome self-sorting nanodegraders for clearing pathogenic factors from serum and treating immune-related diseases driven by these factors.”
Capturing harmful immune molecules in the bloodstream
The nanoparticles engineered by Wu, Pu and their colleagues have two main layers. The first is a rigid, SP-based inner core that helps them travel inside cells and reach lysosomes. The second is an outer coating that captures molecules in the bloodstream and is based on PEG, a biocompatible polymer widely used for biomedical applications.
“SOLID’s unique rigid core (mean Young’s modulus of 3.57 GPa) exerts greater mechanical stress on the cell membrane, facilitating membrane wrapping and clathrin recruitment, which drive NP uptake via clathrin-coated pits and thereby confer near-quantitative lysosomal accumulation,” explained Pu. “The PEG shell is highly customizable, allowing its target-binding modules to be tailored to different targets.”
To eliminate harmful molecules in the bloodstream, SOLID nanoparticles undergo three key phases. First, the nanoparticles circulate in the blood and capture pathogenic molecules. These molecules, along with other proteins in the blood, also stick to the nanoparticles’ surface, creating a coating known as a ‘protein corona.’
Subsequently, two proteins, ApoE and C3, mediate the preferential accumulation of SOLIDs in the liver and spleen, respectively. Approximately 91.6% of the SOLID content accumulates in the liver, and 5.5% in the spleen. Once inside the liver, SOLIDs are swallowed by specific liver cells (i.e., hepatic cells) that contain significantly more lysosomes than cells in other organs.
As part of their recent study, the team carefully engineered the SOLID nanoparticles’ PEG shell using specific antibodies and nucleic acid strands to ensure that they captured two known immune mediators, namely cytokine IL-6 and oligonucleotide CpG1826. They then tested the nanoparticles in mouse models of sepsis and acute lung injury.
The results of their initial experiments were promising. SOLIDs were found to effectively dispose of more immune mediators in the mice’s blood than other antibody-based and LYTAC-based therapies and treated mice with sepsis and acute lung injury-like conditions more effectively.
“Our work emphasizes NP mechanics as a key determinant of organelle targeting, establishes the liver as the principal site for lysosomal degradation and offers a new route to treat disease by clearing pathogenic serum mediators,” said Pu.
“Whereas NPs have traditionally been used primarily as drug carriers, we identified the intrinsic mechanical properties of SOLIDs as the key determinant of their lysosome-targeting ability, thereby transforming the intrinsic properties of NPs into a therapeutic component.”
Initial findings and possible clinical applications
The recent efforts by Pu’s team and their collaborators could potentially open new opportunities for treating conditions associated with heightened immune responses and the accumulation of immune mediators in the bloodstream. Notably, tests in different animals suggest that the SPs used by the team are biocompatible and do not interfere with physiological functions.
“Viral infections and cancer immunotherapies may trigger excessive immune activation, leading to cytokine storms and the accumulation of pathogenic mediators in the serum,” said Pu. “SOLIDs can be tailored into personalized nanodegraders for individual patients, enabling the selective degradation of specific cytokines and thereby preventing organ damage caused by systemic hyperinflammation.”
Before the team’s nanoparticles can be tested in human clinical trials, their safety and effectiveness will need to be further validated. Meanwhile, the researchers are exploring the possibility of directing SOLIDs to other organs to treat organ-specific conditions.
“In this study, SOLIDs were primarily designed to target the hepatic lysosomes to maximize the degradation of serum pathogenic biomolecules,” added Pu.
“In future studies, modulating the organ distribution of SOLIDs to address organ-specific diseases driven by different pathogenic mediators may represent a promising research direction. Such organ-selective SOLIDs can specifically accumulate in diseased organs or tissues and degrade pathogenic mediators in situ.” https://phys.org/news/2026-07-nanoparticles-immune-molecules-blood.html
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