2. Academic Validation
  3. Trafficking Glycogen Nanoparticles through Lymph Node Tissues for the Delivery of Small and Large Bioactive Molecules

Trafficking Glycogen Nanoparticles through Lymph Node Tissues for the Delivery of Small and Large Bioactive Molecules

  • ACS Nano. 2025 Oct 30. doi: 10.1021/acsnano.5c13134.
Soraia Fernandes 1 2 3,  Rong Xu 4,  Robert De Rose 1,  Yuang Gu 1,  Alessandra Dominicis 1,  Sukhvir Kaur Bhangu 1,  Haleh Mahmoudinoodezh 2,  Haiyan Zhu 2,  Giancarlo Forte 3 5 6,  Christoph E Hagemeyer 4,  Frank Caruso 1,  Francesca Cavalieri 1 7
Affiliations

Affiliations

  • 1 Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
  • 2 School of Science, RMIT University, Melbourne, Victoria 3000, Australia.
  • 3 International Clinical Research Center, St. Anne's University Hospital, 60200 Brno, Czech Republic.
  • 4 School of Translational Medicine, Monash University, Melbourne, Victoria 3004, Australia.
  • 5 School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London SE5 9NU, U.K.
  • 6 Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
  • 7 Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.
PMID: 41165268 DOI: 10.1021/acsnano.5c13134
Abstract

Targeted delivery of therapeutics to lymph nodes (LNs) via minimally invasive subcutaneous injection offers promise to treat B and T cell malignancies, latent HIV-1 reservoirs, and Cancer metastasis. However, achieving therapeutic drug levels in subcutaneous tissues and LNs is challenging because of the poor retention and accumulation of soluble drugs. Engineered nanoparticles (NPs) provide a platform for prolonging drug stability and retention in the subcutaneous space and LNs, acting as reservoirs for the sustained release of drugs through the lymphatic system. Yet, their clinical translation for LN drug delivery faces limitations owing to the potential immunogenicity and toxicity of NP material components. Herein, we show that glycogen, a natural and biodegradable polysaccharide NP can be tailored by controlling its size, surface charge, and functional groups to enable the delivery of small and large bioactive molecules in LNs. Upon subcutaneous injection, positively charged glycogen NPs primarily accumulate in the liver and kidneys, whereas negatively charged glycogen NPs accumulate in the liver and lungs, irrespective of their size. Small and positively charged (19 ± 2 nm in diameter; 53 ± 4 mV) glycogen NPs accumulate more efficiently in LNs than the large and positively charged (57 ± 2 nm in diameter; 54 ± 9 mV) or small and negatively charged (13 ± 4 nm in diameter; -27 ± 1 mV) glycogen NPs. Moreover, smaller and slightly positively charged glycogen NPs (16 ± 4 nm in diameter; 10 ± 6 mV) enable the loading and delivery of Cre-recombinase mRNA, small organic molecules and antibodies at the site of injection and LNs. The glycogen NPs are associated with macrophages lining the subcapsular sinus and medullary regions of the LNs but are also detected within the paracortex at the T cell zone. This suggests that the glycogen NPs can overcome the phagocytic cell barrier by saturating the phagocytic capacity of the macrophages at the subcapsular sinus and spread to deeper parts of the paracortex region, providing an avenue for their application in the treatment of lymphatic diseases.

Keywords

glycogen nanoparticles; lymph node trafficking; mRNA delivery; paracortex accumulation; small molecule delivery.

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