Antibiotic resistance is a growing concern – from human health to crop survival. A new study successfully uses nanogels to target and almost entirely inhibit the bacteria P. Aeruginosa. 

Recently published in Angewandte Chemie, the study demonstrates 99.9 % effective inhibition against P. Aeruginosa, a particularly evasive bacterium.

By combining pathogen-specific sugar ligands with a membrane-disrupting antimicrobial peptide, the system shows strong efficacy against both planktonic bacteria and established biofilms: two environments where conventional antibiotics often fail.

P. aeruginosa is a leading cause of hospital-acquired infections, especially in immunocompromised patients. Its ability to form biofilms enables it to evade antibiotics and immune responses.

In this study, nanogels are presented as a promising workaround to this challenge. Their tunable structures support multifunctionality, making them suitable for carrying therapeutic agents and enabling multivalent interactions that enhance microbial targeting.

The researchers constructed their nanogels using dendritic polyglycerols (dPGs) functionalized with two sugars: fucose (Fuc) and galactose (Gal) ligands. The sugars bind to the P. aeruginosa lectins LecB and LecA, and are then integrated into the antibacterial peptide BMAP-18 (GRFKRFRKKFKKLFKKLS), known for its membrane-disrupting activity.

This framework hopes to break down the protective membrane that enables P. aeruginosa to thrive despite other antibiotics, and then inhibit the bacterial almost completely.

The nanogels were synthesized using photo-induced thiolene crosslinking of norbornene and thiol-bearing dPG macromonomers using inverse nanoprecipitation.

Among several different formulations, NG0.33 (the nanogel formulation with a 33 % macromonomer ratio) exhibited the strongest intrinsic binding to bacteria. The researchers attribute this success to the optimized flexibility, making it the chosen scaffold for further modification.

After conjugation with sugars and BMAP-18, nanogel size increased from 47 nm to about 80 nm, and zeta potential rose from +35 mV to +45 mV, confirming successful functionalization.

Importantly, the nanogels remained structurally stable across infection-relevant pH values (5.0-7.0) for at least five days.

Near Perfect Performance Against Planktonic Cells and Biofilms

The sugar-modified nanogels showed higher affinity for both planktonic and biofilm-associated P. aeruginosa in flow cytometry and fluorescence microscopy assays. Significantly, the results of the study showed that adding BMAP-18 did not interfere with lectin binding.

At just 8 µg/mL, the peptide-sugar nanogels (PNG0.33-Fuc/Gal) inactivated over 99.99 % of planktonic bacteria within 12 hours and maintained continued bactericidal activity for more than 72 hours.

Control experiments also demonstrated that sugar-only nanogels could initially reduce bacterial survival, but bacteria resumed growth over time, highlighting the need for a combined targeting-and-killing strategy.

For biofilms, the same nanogels achieved near-complete matrix removal after 72 hours of co-incubation and reduced the thickness of mature 72-hour biofilms by 65 % after a 12-hour treatment, performance comparable to tobramycin.

More than 99.9 % of the biofilm-embedded P. aeruginosa cells were inactivated, indicating efficient penetration and disruption of the biofilm structures.

Broad-Spectrum Potential and Biocompatibility

The nanogels were also effective in inhibiting other bacterial growth: they achieved approximately 90 % inhibition of E. coli and MRSA at higher doses (32 µg/mL and 16 µg/mL, respectively).

This activity likely reflects the higher natural affinity of galactose for lectins in these bacteria, combined with BMAP-18’s membrane activity.

Biocompatibility tests demonstrated over 80 % fibroblast viability at concentrations up to 1 mg/mL, with no measurable hemolysis, indicating a favorable safety profile for further preclinical exploration.

A Modular Platform for Next-Generation Antimicrobials

By integrating lectin-targeting sugars with a potent antimicrobial peptide, the heteromultivalent nanogels address weaknesses of single-function systems and highlight the advantages of combining selective recognition with sustained bactericidal action.

Their modularity suggests they could be adapted to target other pathogens by varying ligand or peptide components.

Future work will first need to evaluate in vivo performance, as well as manufacturing scalability and expanded ligand-peptide combinations.

As antibiotic resistance continues to rise, such customizable nanogel systems are a compelling first step in anti-infective medicines.

Journal Reference

Yuhang, J.D., et al. (2025, November). Heteromultivalent Nanogels as Highly Potent Inhibitors of Pseudomonas Aeruginosa. Angewandte Chemie International Edition, e13121. DOI: 10.1002/anie.202513121

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