Multi-bioresponsive silk fibroin-based nanoparticles with on-demand cytoplasmic drug release capacity for CD44-targeted alleviation of ulcerative colitis

The requirement for the favorable therapeutics against ulcerative colitis (UC) is that anti-inflammatory drugs can be specifically internalized by macrophages and subsequently be on-demand released to suppress inflammation. Herein, we developed a type of multi-bioresponsive anti-inflammatory drug (curcumin, CUR)-loaded nanoparticles (NPs) that were derived from natural silk fibroin and followed by surface functionalization with chondroitin sulfate (CS). The generated CS-CUR-NPs had a desired average particle size (175.4 nm), a uniform size distribution and negative surface charge (-35.5 mV). Strikingly, these NPs exhibited excellent bioresponsibility when triggered with the intrinsic stimuli (acidity, glutathione and reactive oxygen species) within activated macrophages, indicating that they could conceivably confer the on-demand intracellular drug release. Furthermore, we found that CS functionalization yielded notably targeted drug delivery to macrophages, and thereby enhanced the anti-inflammatory activities of NPs. Most importantly, animal experiments revealed that these nanotherapeutics could remarkably alleviate the symptoms of UC, maintain the homeostasis of intestinal microbiota and improve the survival rate of mice with UC through the route of oral administration or intravenous injection. Our results suggest that these facilely fabricated CS-CUR-NPs, which exhibit excellent biocompatibility, multi-bioresponsive drug release and macrophage-targeted capacity, could be exploited as a promising therapeutic platform for clinical UC treatment.