Physically crosslinked agarose–hyaluronic acid hydrogel for injectable treatment of photoaged skin

Prolonged ultraviolet (UV) exposure leads to photoaging characterized by collagen degradation, oxidative stress, and impaired skin barrier function. Injectable hydrogels offer a minimally invasive strategy for dermal repair, but conventional materials often rely on chemical crosslinkers, raising concerns over biosafety and long-term biocompatibility. Herein, we develop a physically crosslinked agarose–hyaluronic acid (Aga–HA) composite hydrogel derived from marine-sourced Gelidium agarose and optimized with 0.5% HA. The resulting Aga–0.5% HA hydrogel exhibits shear-thinning behavior, enhanced injectability, low swelling, and improved acid resistance without chemical modification. Spectroscopic and thermal analyses reveal that HA incorporation disrupts agarose double-helix packing via hydrogen bonding, forming a flexible and porous network. In vitro, the hydrogel promotes human dermal fibroblast proliferation and displays excellent cytocompatibility. In vivo, it demonstrates non-pyrogenic and non-hemolytic behavior, enhances tissue hydration, and accelerates regeneration in zebrafish and murine photoaging models. Importantly, Aga–0.5% HA restores dermal density, improves collagen deposition, reduces inflammation, and attenuates oxidative stress. This biocompatible, chemically crosslinker-free hydrogel offers a safe and effective injectable platform for treating photoaged skin and regenerating soft tissue.