Wrapping LL-37 in hyaluronic acid nanogels kept 36% more of the antimicrobial peptide in the lungs while reducing its accumulation in the liver and kidneys.
36% more retentionNanogel encapsulation kept 36% more LL-37 in the lungs compared to free peptide, while reducing the amount reaching excretory organs
What the researchers found
Encapsulating LL-37 (the only human cathelicidin antimicrobial peptide) in hyaluronic acid-based nanogels increased its retention in the lungs by 36% compared to unformulated LL-37 after intratracheal administration. Without nanogel protection, approximately 85% of LL-37 was cleared from the lungs within 48 hours. The nanogel formulation also reduced the amount of peptide reaching the liver and kidneys, potentially decreasing the toxicity risks associated with high-dose antimicrobial peptide therapy.
The researchers used radiolabeled tracking (67-gallium for LL-37, 111-indium for the nanogel polymer) with SPECT/CT imaging to non-invasively monitor both the peptide and its carrier in real time in mice.
Why it matters
Antimicrobial peptides like LL-37 are promising weapons against antibiotic-resistant bacteria, but they break down too quickly in the body and can damage the liver and kidneys at the high doses needed. This nanogel approach solves both problems simultaneously — keeping more peptide in the lungs where it's needed while reducing how much reaches organs where it causes harm. This could make inhaled LL-37 a viable treatment for lung infections.
The numbers in context
85% of free LL-37 cleared from lungs in 48 hr · Nanogel increased lung retention by 36% · Reduced peptide in liver and kidneys · 67Ga-labeled LL-37 · 111In-labeled HA-OSA nanogel · SPECT/CT tracking in mice
How the study worked
Researchers created nanogels from hyaluronic acid modified with octenyl succinic anhydride (HA-OSA) and loaded them with LL-37. Both the peptide and the carrier polymer were radiolabeled with different isotopes, enabling dual-tracked SPECT/CT imaging in mice after intratracheal administration. The biodistribution of LL-37 was compared between nanogel-encapsulated and free peptide over 48 hours, measuring retention in the lungs and accumulation in excretory organs.
Who was studied
Mice (intratracheal administration, SPECT/CT imaging)
What this study cannot tell us
This is an animal study in mice with pharmacokinetic tracking — it did not test whether the nanogel-formulated LL-37 was actually more effective at killing bacteria in lung infections. The antibacterial efficacy of the encapsulated peptide in vivo was not assessed. Mouse lung anatomy differs from human lungs, and scaling inhaled delivery to humans is challenging.
How to read the evidence
This is a preclinical animal study focused on pharmacokinetics and biodistribution. It provides strong proof-of-concept for the delivery system but does not demonstrate antibacterial efficacy or clinical outcomes.
When this study was published
Published in 2025, this is a cutting-edge study using state-of-the-art dual-isotope SPECT/CT imaging to track peptide delivery in real time.
The bigger picture
As antibiotic resistance grows, antimicrobial peptides like LL-37 are increasingly viewed as next-generation antibiotics. But the gap between a peptide's killing power in a lab dish and its effectiveness in the body is largely a delivery problem. This nanogel approach addresses the two biggest barriers — rapid degradation and organ toxicity — and could help bring inhaled antimicrobial peptide therapies to clinical reality for treating pneumonia and other lung infections.
Questions still open
- Does the nanogel-encapsulated LL-37 actually kill bacteria more effectively in vivo than free LL-37?
- Could this nanogel delivery system be adapted for other antimicrobial peptides beyond LL-37?
- What is the long-term safety profile of repeatedly inhaling hyaluronic acid-based nanogels?
Common questions
Why can't LL-37 just be inhaled directly?
What is a nanogel?
Read the original research
Nanogel encapsulation improves pharmacokinetics and biodistribution of antimicrobial peptide LL37 upon lung deposition: In vivo evaluation by SPECT/CT.
Journal of controlled release : official journal of the Controlled Release Society, 383, 113817
Citation
Kłodzińska, Sylvia N; Esposito, Tullio V F; Agnoletti, Monica; Rodríguez-Rodríguez, Cristina; Blackadar, Colin; Wu, Lan; Thakur, Aneesh; Nahrstedt, Jessica; Rades, Thomas; Saatchi, Katayoun; Häfeli, Urs O; Mørck Nielsen, Hanne. (2025). Nanogel encapsulation improves pharmacokinetics and biodistribution of antimicrobial peptide LL37 upon lung deposition: In vivo evaluation by SPECT/CT.. Journal of controlled release : official journal of the Controlled Release Society, 383, 113817. https://doi.org/10.1016/j.jconrel.2025.113817