M cell-mediated lymphatic route for Radix Astragali polysaccharide to initiate immune response

The gut wall acts as a barrier to large molecules, making it difficult for developing orallydelivered macromolecular therapeutics. Some polysaccharides can quickly affect the immune system after oral dosing, but the mechanisms underlying these effects remain elusive. The mystery of how orally administered polysaccharides exert their therapeutic effects has been a long-standing challenge. Recently, we reveal a unique lymphatic route for Radix Astragali (Huang Qi) polysaccharides (RAP), offering exciting implications for immune-boosting therapies. We first demonstrated the immune-dependent antitumor activity of RAP in vivo, where RAP’s effects were abolished in immunodeficient nude mice. Importantly, we found that RAP remains intact in the small intestine and quickly enters Peyer’s patches (PPs). Within the PP, RAP selectively targets follicle dendritic cells (FDCs), key antigen-presenting cells that orchestrate immune responses. This targeted interaction triggers a cascade of immune activation. This discovery illuminates a unique lymphatic route through which RAP can directly contact immune cells. These findings not only bridge the gap between in vitro and in vivo studies of RAP but also propose a potential mechanism applicable to a broader range of bioactive polysaccharides. The remarkable selectivity of RAP for PPs led to investigations into the underlying cellular mechanisms. PPs possess specialized microfold cells (M cells) known for their ability to transport antigens and pathogens from the gut to the underlying lymphoid tissue. Evidence now points to M cells as the key facilitators of RAP's entry into PPs. Using an in vitro M cell model, efficient transport of RAP was confirmed. In vivo studies further revealed clear co-localization of RAP with M cells within PPs. Critically, these findings have been translated to human intestinal samples, confirming the M-cell-mediated uptake in humans and reinforcing the clinical relevance of this discovery. M cells appear to be essential gatekeepers, granting RAP access to PPs and driving its immunomodulatory and antitumor effects. This breakthrough discovery unveils the intricate mechanism by which orally administered RAP interacts with the immune system, paving the way for the development of next-generation oral polysaccharide-based therapeutics and vaccines.