Hyaluronic acid-based CeO₂ nanozymes for brain-targeted Parkinson's disease therapy: Biointerface design, multifunctional neuroprotective regulation and future perspectives: A review.
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder driven by oxidative imbalance, mitochondrial dysfunction, and persistent neuroinflammation, yet current pharmacological interventions provide symptomatic relief but fail to halt neuronal degeneration largely owing to complex pathological mechanisms and poor blood-brain barrier (BBB) penetration. Cerium oxide (CeO₂) nanozymes have garnered considerable attention for their reversible Ce3+/Ce4+ redox cycling and intrinsic superoxide dismutase (SOD) and catalase (CAT)-like activities, although therapeutic efficacy is restricted by insufficient brain accumulation and limited nano-bio interface interactions. Hyaluronic acid (HA), a naturally occurring polysaccharide, has emerged as a bioactive macromolecule for nano-bio interface engineering, enhancing colloidal stability, biological recognition, cellular uptake, and brain-targeting efficiency of CeO₂ nanozymes via cluster of differentiation 44 (CD44)-mediated targeting of activated microglia. This review systematically summarizes recent advances in HA-CeO₂ nanozyme platforms for PD therapy, with key findings indicating multifaceted neuroprotection through modulation of oxidative stress (Nrf2/ARE), mitochondrial dysfunction (PINK1/Parkin), neuroinflammation (NF-κB/NLRP3), α-synuclein pathology (autophagy-lysosomal pathways), and ferroptosis (Nrf2/SLC7A11/GPX4). Structure-activity relationship analyses reveal that CeO₂ core properties and HA characteristics collectively determine catalytic activity and targeting efficiency. Significant limitations persist, including insufficient structural-efficacy correlations, unclear long-term biosafety, and lack of standardized protocols. By highlighting HA as a bioactive polysaccharide that governs nano-bio interface regulation, this review provides a biomacromolecule-oriented perspective for designing brain-targeted CeO₂ nanozyme platforms, while critically examining the translational barriers that must be overcome to realize their clinical potential.