Probiotics with Emodin-nanobackpack restore goblet cell-dependent mucus layer integrity via colonic patches to ameliorate ulcerative colitis.

While mucosal layer restoration is one of the key therapeutic goals for ulcerative colitis (UC), the current clinical treatments, including probiotics and therapeutic agents, fail to achieve it. As mucosal integrity often depends on goblet cell (GC) abundance and mucus secretion capability, herein we developed LEG@PDA, an orally delivered probiotics-nanotherapeutic system, composed of Lactobacillus rhamnosus GG (LGG) backpacked with emodin-loaded lactoferrin nanoparticles (LENs) and surface-coated with polydopamine (PDA). The outer layer PDA provides gastric protection and colon-targeted delivery, while LENs exhibit lactoferrin-mediated targeting to colonic epithelial cells, concurrently suppressing ferroptosis through iron homeostasis modulation, mitochondrial stabilization, and GSH-GPX4 axis activation. This significantly increases GC population, providing a cellular reservoir for enhanced mucus secretion. Simultaneously, LGG is delivered to colonic patches through M cell-mediated transcytosis, where it orchestrates mucus extrusion of GC via the CGRP-RAMP1 axis. In murine models, LEG@PDA exhibited excellent efficacy in UC management and preventing disease relapse. This strategy, combining probiotics and natural compound-loaded nanobackpacks, offers a practical and targeted approach to restore the GC-dependent mucosal layer via Colonic patches, presenting a promising advance for effective UC treatment.