(a) Schematic of fabricating a stable ion-pair network by mixing polycations and polyanions followed by crosslinking. (b) Cartoon illustration of the ion-pair network cloak. (c) Time-dependent blood concentrations of nanomachines coated with ion-pair networks of different crosslinking degrees. (d) Comparison of the ion-pair network cloak with the conventional PEG cloak. Credit: Kyushu Univ. and iCONM

Japan’s Innovation Center of NanoMedicine reports on a new stealth coating for tiny medicine-carrying particles that doesn’t depend on PEG-style shields. By locking positive and negative charges together into a tight net, the coating prevents protein buildup and avoids pickup by immune cells, so the particles stay in the blood for more than 100 hours. Packed with the enzyme asparaginase, the particles act like small reactors that drain asparagine to starve difficult-to-treat cancers.

Stealth in nanomedicine refers to avoiding unwanted sticking to proteins and less attention from immune cell attacks, allowing the particles to keep moving through the bloodstream.

Current high-energy nanoparticle surfaces allow particles to stick to proteins and cells, which limits some medical uses. PEG (polyethylene glycol) coatings and similar hydrophilic shells are the main workaround, using steric repulsion, yet getting PEG to work well often needs careful tuning of density and chain length and many particles still escape quickly when exposed to blood.

In the study, “Steric stabilization-independent stealth cloak enables nanoreactors-mediated starvation therapy against refractory cancer,” published in Nature Biomedical Engineering, researchers engineered polyion complex micelles and vesicles with tunable crosslinks to test whether a stabilized ion-pair network can reduce protein adsorption and macrophage uptake and enable long-circulating asparaginase nanoreactors for asparagine starvation therapy, in mice.

Engineering stealth

Researchers assembled polyion complex micelles of about 30 nm and vesicles of about 100 nm by mixing polycations and polyanions at equimolar charge ratio for 2 min, then introduced covalent crosslinks via a carbodiimide compound widely used to link carboxyl and amine groups in biochemistry, to form covalent crosslinks that stabilize the charged polymer network. Stability to high salt was maintained with modest crosslinking and shape remained unchanged.

Stealth thresholds and outcomes

Researchers report sharply reduced protein adsorption and macrophage uptake once crosslinking crossed defined thresholds: 39.5% for micelles and 30.3% for vesicles. Vesicles with 32.6% crosslinks and no PEG showed minimal protein binding and remained “invisible” to macrophages. Blood half-life rose from minutes to long single-phase values once thresholds were exceeded, reaching 121.5 h for micelles at 39.5% and 97.2 h for vesicles at 30.3%.

Fluorescence correlation spectroscopy showed diffusion times in 100% serum matching buffer after crosslinking surpassed the thresholds, consistent with little protein adsorption. Isothermal titration calorimetry recorded no detectable heat for M39.5%, V30.3%, and the 32.6% dePEGylated vesicle, again consistent with minimal protein binding.

Therapeutic efficacy of the asparaginase-loaded stealth nanoreactor (ASNase@V) in metastatic triple-negative breast cancer (TNBC). Credit: Kyushu Univ and iCONM

In vivo interaction and clearance

Intravital liver imaging showed rapid adhesion of low-crosslinked particles to sinusoidal walls and strong uptake by CD45+ F4/80+ macrophages and CD45− cells. Long-circulating particles resided within the sinusoidal lumen without sticking and accumulated in the liver only slowly. Thirty-nanometer micelles crossed fenestrated endothelium and moved toward hepatobiliary excretion, while 100 nm vesicles showed slow capture by macrophages over time.

Biodistribution and prolonged intravital tracking supported those routes. Flow cytometry and section staining corroborated macrophage association for vesicles and limited macrophage association for micelles at long time points.

Tumor therapy effects

Asparaginase-loaded vesicles maintained long circulation and produced sustained asparagine depletion in plasma and tumors. Dosing yielded more than 50% depletion at 4 h and about 80% at 96 h in plasma, with intratumoral reductions also reported.

Metastatic breast cancer models showed reduced primary tumor weight and fewer lung nodules with the nanoreactor regimen compared with free enzyme. Pancreatic tumors showed lower collagen I deposition and fewer αSMA-positive fibroblasts after nanoreactor treatment, with greater anti-PD-1 immunotherapy penetration through tumor tissue and improved efficacy when combined with anti-PD-1.

At a glance

A cooperative ion-pair network sheath can produce stealth without using the usual PEG coating. Findings introduce a route to keep the material stable and less “sticky,” helping the particles circulate longer while avoiding detection and attacks from the immune system longer.

In mice, enzyme-loaded stealth vesicles remained active in the body and deprived tumors of asparagine, weakening their growth. Treatment also softened the dense tissue around pancreatic tumors and made immune drugs like anti–PD-1 work better.

Observations also suggest a size threshold for crossing liver endothelium with 30 nm micelles versus 100 nm vesicles, and propose an unexpected mechanism for why some PEG-coated nanoparticles may last in blood.

Written for you by our author Justin Jackson, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.

More information: Junjie Li et al, Steric stabilization-independent stealth cloak enables nanoreactors-mediated starvation therapy against refractory cancer, Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01534-1

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Citation: Ion-pair stealth shield hides nanoparticles from the body’s defenses (2025, November 10) retrieved 10 November 2025 from https://phys.org/news/2025-11-ion-pair-stealth-shield-nanoparticles.html

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