A Novel Nanoparticle Strategy to Deliver Locally High Concentrations of Active Vitamin D and Retinoic Acid to Enhance Gut Immune Tolerance 2259162

Abstract Introduction Despite promises in treating many diseases, active vitamin D and retinoic acid (RA) face a formidable barrier in clinical application due to severe side effects associated with the systemic high concentrations usually required for therapeutic efficacy. We recently propose that de novo synthesis of locally high concentrations of these two molecules is a potential solution because of their short half-lives, which can prevent systemic concentration surges while still maintaining therapeutic concentrations locally. Methods We previously evaluated one strategy that overexpressed two physiological enzymes in activated dendritic cells (DCs): the 1alpha-hydroxylase that synthesizes active vitamin D, and the retinaldehyde dehydrogenase 2 (RALDH2) that synthesizes RA. We showed that the engineered DCs, when injected, homed to peripheral lymphoid tissues and de novo synthesized locally high concentrations of the two molecules without significant side effects, leading to robust suppression of experimental colitis by augmenting the induction of gut-homing CD4 Treg, consistent with other reports that active vitamin D at high concentrations induces regulatory molecules (Foxp3 and IL-10) and RA gut-homing receptors. However, DC-based therapy entails technological challenges and high costs. Here, we report a novel engineered nanoparticles that deliver the genes of 1apha-hydroxylase and RALDH2 specifically to DCs in vivo. Results Our data showed that intravenous injections of the engineered nanoparticles significantly upregulated the expression of 1apha-hydroxylase and RALDH2 and increased the local concentrations of these two molecules in tissues. In vitro, the nanoparticle-loaded DCs programmed gut-homing CD4 Treg and suppressed the proliferation of autologous CD4 T cells. Conclusion Our data suggests that such engineered nanoparticles are a potential cure for intestinal inflammation, e.g., canine inflammatory bowel disease. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)