Nanoparticles Bearing Siglec Ligands

A potential platform for multivalent glycan display in C-type lectin receptor (CLR) targeting and imaging is now nanoparticles. Positive results from selectin inhibition in cancer have reenergized the field and prompted more selectin-targeting research. These strategies consist of chimeric antigen receptor (CAR) T cells with forced expression of sLex to promote E-selectin ligand display and improve infiltration into the marrow, as well as nanoparticles coated with P-selectin ligands for targeted drug administration. By aggregating, nanoparticles like liposomes containing Siglec ligands may aggravate Siglecs or be used to deliver specific payloads.

Fig.1 Nanoparticles decorated with synthetic Siglec ligands engage. (Smith & Bertozzi, 2021)

Potential Applications of Nanoparticles Bearing Siglec Ligands

Due to their distinctive pattern of expression on different subsets of white blood cells and their ability to carry therapeutic cargo into the cell via endocytosis, the Siglec family of sialic acid-binding proteins provides an alluring class of therapeutic targets. Because of this, approaches to using Siglecs for targeted-cell treatments are being studied more and more in order to treat illnesses ranging from allergies to cancer. As an alternate platform for targeting Siglecs to antibodies used in first-generation techniques, liposomal nanoparticles coated with Siglec ligands have shown promise since they are simple to load and carry a range of therapeutic payloads.

Fig.2 Overview of carrier systems used for multivalent glycan display. (Kim, et al., 2020)

Examples of Nanoparticles Bearing Siglec Ligands in Therapies

• High-mannose oligosaccharides and Lewis-type moieties, such as Lewis x (Lex) and Lewis b, are natural ligands for the C-type lectin DC-SIGN (Leb). Since the carbohydrate recognition domain of DC-SIGN mediates the identification of carbohydrate antigens, globular nanoparticles that resemble the physiological glycoproteins of pathogens have been proposed as a smart platform to target DC-SIGN.
• Strongly anti-inflammatory poly (lactic-co-glycolic acid) nanoparticles coated with 2-8 sialic acids have the potential to reduce pathophysiology in a number of LPS-induced sepsis models by activating Siglec-E and increasing IL-10 production in mice macrophages.
• In mice, B lymphocytes lacking CD22 and Siglec-G (a human Siglec-10) are overactive and exhibit autoimmune characteristics. In mice models of sepsis and acute respiratory distress syndrome, nanoparticles coated with α-2,8-linked disialic acid worked as Siglec agonists and increased survival.
• PEGylated and further mannosylated hydroxyethyl starch nanocarriers on the outer polyethylene glycol (PEG) layer. These mannosylated nanocarriers demonstrated strong dendritic cell (DC) targeting effectiveness with no non-specific protein adsorption, making them potentially useful in vivo.
• The creation of core-shell superparamagnetic silica glyconanoparticles that bound to P- and E-selectin on endothelial cells. These particles were tested in an animal stroke model that is therapeutically applicable, and it was discovered that they accumulated in the brain's blood vessels.

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References:

1. Kim, B. et al. Identification of a moderate affinity CD22 binding peptide and in vitro optimization of peptide-targeted nanoparticles for selective uptake by CD22+ B-cell malignancies. Nanoscale. 2020, 12(21): 11672–11683.
2. Smith, B.A.; and Bertozzi, C.R. The clinical impact of glycobiology: Targeting selectins, Siglecs and mammalian glycans. Nature Reviews Drug Discovery. 2021, 20(3): 217–243.