In situ Gel–Nano transformable hydrogel for therapeutic intervention in refractory inflammation-related trauma

In this study, we introduce a novel injectable hydrogel, termed hDAGel, which exhibits a unique gel-to-nano (Gel-Nano) configuration inversion capability in response to local pathological microenvironments. The hydrogel is formulated with a high loading density of dopamine, serving the dual function: an injectable dual-component drug-loading gel and triggering the in situ formation of drug-loaded polydopamine-based nanoparticles upon dopamine release and oxidative polymerization. This Gel-Nano transformation enables sustained and targeted drug delivery precisely at inflamed or injured sites. Moreover, hDAGel effectively scavenges excess reactive oxygen species (ROS) within inflamed tissues, alleviating oxidative stress and modulating immune responses. Upon local administration, such as intracerebral injection for cerebral ischemia or topical/intradermal application for allogeneic skin transplantation, hDAGel persists at the target site and dynamically responds to microenvironmental stimuli, releasing therapeutic nanoparticles that suppress inflammation and immune overactivation. Collectively, hDAGel integrates the advantageous features of injectable, adhesive hydrogels with the precise and controlled release of nanoparticle-delivered therapeutics via Gel-Nano transformation. This multifunctional platform holds great promise for treating complex inflammation-associated conditions, including neuroinflammation and transplant rejection, by providing localized, sustained, and responsive therapy with enhanced antioxidant and immunomodulatory effects.