Inflammation-anchored injectable hydrogel integrating pathological nitric oxide scavenging and on-demand drug release...

Inflammatory bowel disease (IBD), encompassing chronic relapsing gastrointestinal disorders, remains a profound clinical challenge because conventional therapeutics are often impeded by systemic off-target toxicities and suboptimal retention at inflamed mucosal sites. Herein, an inflammation-activated and retentive injectable hydrogel is presented, which leverages pathological nitric oxide (NO) overproduction as both a therapeutic target and an autonomous release trigger. An NO-responsive and NO-scavenging polymer (NRSP) incorporating an NO-cleavable o-phenylenediamine (o-PD) motif is formulated into cationic, dexamethasone-encapsulating micelles and electrostatically assembled with anionic hyaluronic acid (HA) to form a shear-thinning hydrogel that facilitates minimally invasive rectal administration and ensures prolonged, localized retention at the inflamed mucosal interface. Upon exposure to the NO-rich inflammatory microenvironment, structural disruption of NO-responsive and NO-scavenging micelles (NRSM) compromises the electrostatic integrity of the HA-micelle network, thereby reducing the storage modulus and accelerating cargo release. In vitro evaluations using lipopolysaccharide-stimulated macrophages demonstrate that NRSM hydrogels effectively reduce intracellular and extracellular NO levels and attenuate pro-inflammatory cytokine secretion. Furthermore, the HA matrix mediates disease-adaptive localization through CD44 receptor recognition and preferential electrostatic adhesion to positively charged inflammatory interfaces, resulting in enhanced colonic retention in DSS-induced colitis models ex vivo. Following rectal administration in DSS-induced mice, NRSM-based hydrogels significantly alleviate disease severity, reduce colonic NO and inflammatory cytokine levels, and rescue mucosal architecture and mucin-associated features. Notably, dexamethasone-loaded NRSM hydrogel exerted the most potent synergistic therapeutic benefit. Overall, this disease-responsive hydrogel platform establishes an effective localized intervention for IBD, merging intrinsic pathological NO scavenging with controlled drug delivery.