Zwitterionic polymers improve the therapeutic effect of silk fibroin-based nanomedicines against ulcerative colitis via the oral route

The efficiency of oral drug delivery for treating ulcerative colitis (UC) is often limited by poor mucus-penetrating capability and inadequate drug accumulation in the colitis tissues. To address these issues, we developed zwitterionic polymer-modified silk fibroin-based nanoparticles (NPs). These NPs exhibited a nanoscale size of approximately 200 ​nm with a highly uniform size distribution and a slight negative surface charge (−10 ​mV). Notably, the zwitterionic NPs demonstrated enhanced mucus-penetrating ability and increased uptake efficiency by macrophages compared with the control NPs, resulting in significant anti-inflammatory and antioxidant activities. In vivo studies further revealed that orally administered zwitterionic NPs preferentially accumulated in colitis tissues and outperformed the clinical drug dexamethasone in terms of anti-inflammatory and mucosal repair effects in both acute and chronic colitis models. These findings suggest that zwitterionic polymer-modified NPs represent a promising oral drug delivery platform for the effective treatment of UC. • Zwitterionic pluronic polymers were synthesized and used to functionalize the silk fibroin-based nanoparticles (SFNPs). • Zwitterionic polymers enhanced the motion of SFNPs in the mucus layer. • Zwitterionic polymers counteracted the negative effects of polyethylene glycol on the cellular uptake of SFNPs. • Zwitterionic functionalization improved the therapeutic effect of SFNPs in the treatment of ulcerative colitis.