Nitric oxide-responsive hyaluronic acid hydrogel microspheres enable anthocyanin protection and inflammation-triggered release.

Anthocyanins are natural polyphenols with notable antioxidant and anti-inflammatory properties, but their poor stability in the gastrointestinal tract severely limits their oral bioavailability. In this study, a nitric oxide (NO)-responsive hydrogel microsphere delivery system based on hyaluronic acid (HA) was developed to achieve inflammation-targeted delivery of anthocyanins. HA was chemically modified with glycidyl methacrylate (GMA) to introduce photo-crosslinkable vinyl groups. Crosslinking with N, N'-(2-amino-1,4-phenylene) diacrylamide (APD), an o-phenylenediamine-derived linker, conferred NO sensitivity. The resulting hydrogel microspheres formed rapidly under visible light and exhibited robust mechanical strength and structural stability, and a high anthocyanin encapsulation efficiency (76.34 %). In vitro digestion simulations demonstrated that the microspheres protected anthocyanins from gastric degradation and enabled sustained release. Under NO-rich conditions, the hydrogel network degraded, leading to accelerated release. Furthermore, in an inflammation-mimicking environment, anthocyanin-loaded microspheres significantly suppressed pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and restored IL-10 expression. This work demonstrates a structurally stable, NO-responsive HA hydrogel platform that enables precise oral delivery of bioactives and holds potential for inflammation-targeted applications.