{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:05:29Z","timestamp":1790805929927,"version":"4.1.0"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Hyaluronic acid (HA) is a key component of the extracellular matrix (ECM). Owing to its anti-inflammatory properties, biocompatibility and ability to contribute to ECM remodeling, HA is considered a promising therapeutic candidate for neurodegenerative diseases. This review summarizes the application of HA to treat Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) and outlines the current understanding of the mechanism of action and strategies for HA-based biomaterial modification. For AD, HA is involved in several mechanisms including stabilizing the perineuronal net, reducing the toxic effects of A\u03b2 and hyperphosphorylated tau, and modulating neuroinflammation through CD44\/RHAMM signaling pathways. HA-based nanoparticles and hydrogels enhance drug delivery across the blood-brain barrier, facilitate A\u03b2 clearance, and enable sustained, controlled release of therapeutic agents. In PD, HA regulates autophagic flux, inhibits \u03b1-synuclein propagation, and remodels the ECM to protect dopaminergic neurons. Modifications such as HA hydrogels with neurotrophic factors improve cell transplantation outcomes, while conjugates enhance mitochondrial targeting and dopamine delivery. While numerous preclinical studies have shown promise, significant challenges remain, including the high variability of HA formulations, limited blood-brain barrier penetration efficiency, and a paucity of well-designed clinical trials to validate preliminary findings. Future directions include standardizing laboratory protocols, developing hybrid systems integrating vascular endothelial growth factor and gene therapy, and adopting a patient-specific approach that leverages HA\u2019s multi-targeted effects on the nervous system.<\/jats:p>","DOI":"10.3389\/fphar.2026.1772172","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:43:35Z","timestamp":1774248215000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hyaluronic acid: emerging roles and biomaterial innovations in Alzheimer\u2019s and Parkinson\u2019s disease therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Yishu","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University","place":["Guangzhou, China"]},{"name":"Shandong Academy of Pharmaceutical Sciences, Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drugs","place":["Jina, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Duan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixuan","family":"Zang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences, Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drugs","place":["Jina, China"]},{"name":"National Glycoengineering Research Center, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences, Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drugs","place":["Jina, China"]},{"name":"School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Lv","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences, Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drugs","place":["Jina, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences, Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drugs","place":["Jina, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6347","DOI":"10.2147\/ijn.S381353","article-title":"Brain targeting of citicoline sodium via hyaluronic acid-decorated novel nano-transbilosomes for mitigation of alzheimer's disease in a rat model: formulation, optimization, in vitro and in vivo assessment","volume":"17","author":"AbouElhassan","year":"2022","journal-title":"Int. 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