Oral administration of TNF-α-modulating probiotics integrated by dual-layered microcapsule for effective treatment of inflammatory bowel disease

Oral probiotic therapy holds great promise for inflammatory bowel disease (IBD) by virtue of its non-invasive nature and ability to modulate inflammation, but its potential remains limited by insufficient probiotic colonization and incomprehensive therapeutic intervention. Herein, we developed a versatile oral-administrated system, termed EcN-Ap@A/H-Ce, designed to combat chronic relapsing IBD by downregulating inflammatory cytokines (e.g., TNF-α) and scavenging reactive oxygen species (ROS). By conjugating TNF-α aptamers to the surface of Escherichia coli Nissle 1917 (EcN) and encapsulating the engineered probiotic into uniform-sized pH-responsive sodium alginate microspheres via microfluidic technology, a dual-layered microcapsule system was further constructed with an outer composite coating of hyaluronic acid (HA) and CeO 2 nanozymes through liquid interface self-assembly. As expected, the system exhibited robust resistance to the harsh gastrointestinal environment. The HA coating enhanced colon-targeting efficiency, while the CeO 2 nanozymes alleviated oxidative stress and promoted EcN-Ap colonization. Concurrently, EcN-Ap neutralized TNF-α, suppressed inflammation, and restored intestinal barrier integrity. In a murine colitis model, the EcN-Ap@A/H-Ce microcapsule revealed a substantially improved therapy than conventional oral-administrated mesalamine and even achieved comparable therapeutic benefits with clinical intravenous-administrated infliximab while avoiding unpleasant invasive administration. Notably, 16S sequencing revealed enhanced gut microbiota modulation, particularly increasing beneficial Akkermansiaceae populations. This multifunctional microcapsule provides comprehensive IBD treatment with low side effects and improved patient compliance, representing a promising non-invasive alternative for the effective management of IBD and other gastrointestinal disorders.