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

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.