Composite hydrogel microspheres modulate intestinal inflammation via releasing HA modified liposomes@4-OI targeting M1 macrophages

4-Octyl itaconate (4-OI) is an effective alkylating agent that modifies cysteine residues on stimulator of interferon genes (STING). By inhibiting STING protein phosphorylation, 4-OI crucially regulates inflammatory responses associated with intra-abdominal infections. However, the therapeutic use of 4-OI is limited by several pharmacological challenges, including poor aqueous solubility, susceptibility to esterase-mediated hydrolysis, and low oral bioavailability. To overcome these challenges, an effective drug delivery system is critically needed. In this work, we designed hyaluronic acid (HA) functionalized liposomes (HA-Lipo@4-OI) for the targeted delivery of 4-OI. To enhance the therapeutic efficacy of the liposomes, we used electrospray technology to fabricate liposome-hydrogel composite microspheres (LHMs). This drug delivery system combined gastric acid resistance with pH-responsive drug release. Upon oral administration, the system effectively protected 4-OI from degradation by gastric juice, enhanced intestinal retention, and enabled sustained drug release. Moreover, the system demonstrated selective targeting toward macrophages, which further improved therapeutic efficacy. When applied to a model of intestinal mucosal injury induced by severe intra-abdominal infection combined with an open abdomen, LHMs@4-OI significantly suppressed systemic inflammation and promoted intestinal mucosal repair. These findings suggest that this composite platform is a promising treatment for intestinal mucosal injury repair. In this study, we successfully constructed a liposome-composite hydrogel microspheres delivery system equipped with 4-OI (LHMs@4-OI) by using thin film hydration and electrospray technology, which effectively solved the challenges of oral delivery of 4-OI and the lack of active targeting of M1 macrophages. In addition, the liposome-composite hydrogel microspheres exhibited anti-digestive properties, enhanced mucosal repair, and exhibited pH-responsive drug release. • A novel drug delivery system of liposome-hydrogel composite microspheres equipped with 4-OI (LHMs@4-OI) was constructed. • HA modification enhances 4-OI concentration at inflammation sites. • 4-OI alkylates STING, inhibiting the STING-TBK1-IRF3 signaling pathway, and promotes intestinal mucosal barrier repair. • LHMs@4-OI demonstrates resistance to gastric digestion and stability at room temperature, addressing traditional formulation challenges. • The RNA sequencing reveals LHMs@4-OI accelerates intestinal mucosal repair by modulating cell adhesion signaling pathways.