This review compiles preclinical evidence that hyaluronic acid (HA)–based biomaterials modulate neuroinflammation, autophagic flux, α‑synuclein propagation, and ECM remodeling while enabling targeted drug/gene delivery and scaffolded cell transplantation in Alzheimer's and Parkinson's disease.

Highlights HA as a multimodal, translationally relevant platform for neuroprotection and targeted delivery in PD (autophagy/α‑synuclein modulation, mitochondrial/dopamine targeting, and cell-supporting hydrogels) but underscores formulation variability and scarce clinical validation, pointing to…

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's disease (AD) and Parkinson's 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 Aβ 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 Aβ clearance, and enable sustained, controlled release of therapeutic agents. In PD, HA regulates autophagic flux, inhibits α-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's multi-targeted effects on the nervous system.