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The combination of clinical drugs targeting different symptoms with smart hydrogels to achieve asynchronous releases is highly translational and challenging. Here, a hierarchical bioactive hydrogel (OACDP) is designed with asynchronous release based on PD pathology. The hydrogel with caffeic acid\u2010grafted polymer main chain is crosslinked using a micellar nanocrosslinker, with sufficient modulus (\u2248167\u00a0Pa), antioxidant activity (&gt;\u00a050%), injectability (30\u2010gauge syringe needle), and shape\u2010adaptability. Each of the three drugs (caffeic acid, fibroblast growth factor 21, and Edaravone) is separately engaged in different micro\u2010 or nanostructures of the hydrogel and released with asynchronous kinetics of first\u2010order release, zero\u2010order release, or matching Korsmeyer\u2013Peppas model. The triple\u2010loaded hydrogel is injected into the brains of PD rats, showing behavioral improvement. Histological analysis revealed that the triple\u2010loaded OACDP hydrogels are effective in achieving immediate neuroprotection, i.e., reduction the loss of tyrosine hydroxylase in substantia nigra compacta and striatum (retained \u224810\u2010fold versus control), decreasing oxidative stress, reducing astrocyte and microglia activation, and stimulating the AMPK\/PGC\u20101\u03b1 axis to regulate the mitochondrial function, providing a multi\u2010dimensional PD therapy. The asynchronous release of OACDP hydrogel provides a new conception for PD treatment and other neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/advs.202412020","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T14:30:08Z","timestamp":1733322608000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Injectable Hierarchical Bioactive Hydrogels with Fibroblast Growth Factor 21\/Edaravone\/Caffeic Acid Asynchronous Delivery for Treating Parkinson's Disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Junpeng","family":"Xu","sequence":"first","affiliation":[{"name":"Affiliated Cixi Hospital Wenzhou Medical University  Ningbo Zhejiang 315300 China"},{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) School of Pharmaceutical Science Wenzhou Medical University  Wenzhou Zhejiang 325000 China"},{"name":"State Key Laboratory of 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