Ferrous sulfate (FeSO)-directed dual-cross-linked hydrogels were designed for application in single-syringe injections. The use of FeSO, rather than other iron salts, can modulate the gelation time and make it available for subcutaneous injection with a single syringe. These hydrogels are based on hyaluronic acid-dopamine (HA-dp) that contain donepezil (DPZ)-entrapping poly(lactic-co-glycolic acid) (PLGA) microsphere (MS). Although DPZ has been administered orally, its sustained release formulation via subcutaneous injection may reduce the dosing frequency for patients with Alzheimer’s disease. The HA-dp conjugate was synthesized via an amide bond reaction for coordination of dp with a metal ion (Fe or Fe) and self-polymerization of dp. The HA-dp/DPZ-loaded PLGA MS (PD MS)/FeSO gel system was considerably hardened via both the coordination of the metal ion with HA-dp and covalent bonding of dp. In addition, a quick restoration of the collapsed gel structure and sustained DPZ release from the HA-dp/PD MS/FeSO structure were achieved. The pharmacokinetic parameters after its subcutaneous injection in a rat indicate the sustained release and absorption of DPZ from the HA-dp/PD MS/FeSO system. The proposed system can be prepared by a simple method and can be efficiently and safely used for the long-term delivery of DPZ after the subcutaneous injection.Copyright © 2020 Elsevier B.V. All rights reserved.