Ginger-derived exosome-like nanoparticles incorporated into hydrogel matrix for enhanced oral delivery of celastrol to alleviate ulcerative colitis

Celastrol (Cel), a highly promising natural product isolated from traditional Chinese medicine, exhibits potent therapeutic efficacy against ulcerative colitis (UC). Nevertheless, its poor colon-targeting efficiency, insufficient capacity to penetrate the intestinal mucus layer, and low cellular internalization significantly compromise therapeutic outcomes in UC treatment. To address these critical limitations, herein we rationally designed a exosome-hydrogel hybrid system (Cel-GDNPs@Gel) by first encapsulating Cel into ginger-derived exosome-like nanoparticles (GDNPs), which were subsequently dispersed within a glycyrrhizic acid (GA) hydrogel matrix. Experimental studies confirmed that GDNPs were successfully isolated and characterized with uniform size distribution and round- or cup-shaped morphology, and Cel was successful encapsulated into GDNPs. The GA hydrogel endowed the system with excellent pH-sensitivity and robust mucoadhesive properties, thereby facilitating enhanced accumulation and prolonged retention at the colon site. Moreover, GDNPs promoted efficient mucus penetration and cellular uptake of Cel. Notably, both GDNPs and GA could exert synergistic therapeutic effects with Cel. Accordingly, in vitro and in vivo studies demonstrated that Cel-GDNPs@Gel significantly alleviated colitis symptoms, suppressed the expression of pro-inflammatory cytokines, attenuated oxidative stress, regulated macrophage polarization, promoted intestinal mucosal barrier repair, and restored intestinal homeostasis. Furthermore, this delivery system exhibited favorable biosafety with no obvious systemic toxicity. Collectively, this multifunctional Cel-GDNPs@Gel platform offers a safe and effective strategy for the oral treatment of UC. Herein we rationally designed a hydrogel-integrated ginger-derived exosome-like nanoparticles system (Cel-GDNPs@Gel) by first encapsulating celastrol (Cel) into ginger-derived exosome-like nanoparticles (GDNPs), which were subsequently dispersed within a self-assembled glycyrrhizic acid (GA) hydrogel matrix. The GA hydrogel displayed excellent pH-responsiveness, enabling enhanced accumulation of Cel in the colon. Meanwhile, the hydrogel component endowed the system with mucoadhesion, thereby significantly prolonging the intestinal retention of Cel. Moreover, the GDNPs facilitated efficient mucus penetration and cellular uptake. Notably, both GDNPs and GA could exert synergistic therapeutic effects with Cel. Accordingly, Cel-GDNPs@Gel significantly alleviated colitis symptoms, suppressed pro-inflammatory cytokine expression, attenuated oxidative stress via inhibiting ROS overproduction, regulated macrophage polarization by restraining M1 polarization, promoted intestinal mucosal barrier repair by up-regulating tight junction proteins, and remodeled gut microbiota to restore intestinal homeostasis. Furthermore, this delivery system exhibited favorable biosafety. Collectively, this multifunctional Cel-GDNPs@Gel platform offers a safe and effective strategy for the oral treatment of UC. Download: Download high-res image (110KB) Download: Download full-size image