"Hitting Two Birds with One Stone" Design of Intestinal Integrin-Targeting and Redox Homeostasis-Regulating Oral Nanotherapy for Ulcerative Colitis

Abstract

Designing highly efficient orally administrated nanotherapeutics with specific inflammatory site-targeting functions in the gastrointestinal (GI) tract for ulcerative colitis (UC) management is a significant challenge. Straightforward and adaptable modular multifunctional nanotherapeutics represent groundbreaking advancements and are crucial to promoting broad application in both academic research and clinical practice. In this study, we focused on exploring a specific targeting modular and functional oral nanotherapy, serving as "one stone", for the directed localization of inflammation and the regulation of redox homeostasis, thereby achieving effects against "two birds" for UC treatment. The designed nanotherapeutic agent OPNs@LMWH, which has a core-shell structure composed of oxidation-sensitive {varepsilon}-polylysine nanoparticles (OPNs) in the core and low-molecular-weight heparin (LMWH) in the shell, exhibited specific active targeting effects and therapeutic efficacy simultaneously. We qualitatively and quantificationally confirmed that OPNs@LMWH possessed high integrin M-mediated immune cellular uptake efficiency and preferentially accumulated in inflamed lesions. Compared with bare OPNs, OPNs@LMWH exhibited enhanced intracellular reactive oxygen species (ROS) scavenging and anti-inflammatory effects. After oral administration of OPNs@LMWH to mice with dextran sulfate sodium (DSS)-induced colitis, robust resilience was observed. OPNs@LMWH effectively ameliorated oxidative stress and inhibited the activation of inflammation-associated signalling pathways while simultaneously bolstering the protective mechanisms of the colonic epithelium. Overall, these findings underscore the compelling dual functionalities of OPNs@LMWH, which enable effective oral delivery to inflamed sites, thereby facilitating precise UC management.