Atmosphere-inspired multilayered nanoarmor with modulable protection and delivery of Interleukin-4 for inflammatory microenvironment modulation

Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironme...
Ausführliche Beschreibung

Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironment and efficient biological performance remain a challenge. Inspired by the multilayered defense mechanism of the earth's atmosphere, we constructed a multilayered protective nanoarmor (NA) for IL-4 delivery (termed as IL-4PEGRA NAs) into an intricate inflammatory microenvironment. The poly(ethylene glycol) (PEG)-ylated phenolic rosmarinic acid (RA)-grafted copolymer contains two protective layers—the intermediate polyphenol (RA molecules) and outermost shield (PEG) layers—to protect the biological activity of IL-4 and prolong its circulation in blood. Moreover, IL-4@PEGRA NAs scavenge reactive oxygen species with the specific release of IL-4 and maximize its biofunction at the site of inflammation, leading to M2 macrophage polarization and downregulation of inflammatory mediators. Simultaneously, gut microbiota dysbiosis can improve to amplify the M2-polarizing effect and inhibit the phosphatidylinositol 3 kinase/Akt signaling pathway, thereby attenuating inflammation and promoting colitis tissue repair. It provides a nature-inspired strategy for constructing an advanced multilayered NA delivery system with protective characteristics and potential for IBD management. Ausführliche Beschreibung