Injectable pH-responsive carboxymethyl cellulose hydrogel for sustained delivery of IL-22 in the treatment of alcoholic liver disease

Alcoholic liver disease (ALD) is a major chronic liver disorder that poses a significant global health burden due to its severe health risks and limited therapeutic options. Although recombinant interleukin-22 (IL-22) is an available therapeutic agent with potent anti-inflammatory and anti-lipid accumulation effects, its application in ALD treatment has been limited by its short half-life. In this study, we developed a carboxymethyl cellulose hydrogel (CMC)-encapsulated system to prolong the half-life of recombinant IL-22, aiming to achieve effective and sustained inhibition of ALD. Recombinant IL-22 was incorporated into CMC (IL-22@CMC) through hydrogen bonding interactions. This system exhibited pH-responsive drug delivery properties and good biocompatibility. IL-22@CMC reduced alanine aminotransferase (ALT) levels from 250 IU/L to 100 IU/L and aspartate aminotransferase (AST) levels from 700 IU/L to 200 IU/L. These levels were significantly lower than those observed with IL-22 alone (160 IU/L and 400 IU/L, respectively), indicating superior therapeutic efficacy in alcoholic liver injury. RNA sequencing analysis indicated that the enhanced inhibitory effect of IL-22@CMC was achieved through suppression of endoplasmic reticulum stress mediated by the AMP-activated protein kinase/sirtuin 1 signaling pathway in ethanol-induced AML-12 cells. By designing a pH-responsive hydrogel, this study integrates therapeutic agents with a hydrogel carrier via hydrogen bonding, thereby providing an effective strategy for developing drug delivery composites for inflammatory diseases.