Encapsulation of CDNF in collagen hydrogels enabled sustained intracerebral delivery that improved motor behavior in a rodent PD model and dose-dependently altered brain N‑glycosylation, particularly core‑fucosylated glycans.

Provides a translationally relevant biomaterial delivery approach for a neurotrophic therapy and links CDNF efficacy to reversible N‑glycome changes, suggesting both a mechanistic readout and potential biomarker for therapeutic development.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the death of dopaminergic neurons in the substantia nigra (SN). Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that is selective for stressed neurons and acts on the endoplasmic reticulum (ER), which is stressed in the pathophysiology of PD, namely in dopaminergic neurons. Additionally, ER stress is intimately associated with dysregulation of N-glycosylation; therefore, the improvement of ER homeostasis is likely to regulate N-glycosylation, recovering the healthy brain N-glycome. Furthermore, encapsulation of CDNF in a hydrogel system for sustained delivery of CDNF at the target site is of interest to prevent its rapid elimination. In this study, a collagen-based hydrogel was optimised to deliver CDNF into the brain of a PD model, and its effects on modulating the animals' functional behaviour and the intrinsic N-glycome of the brain were assessed. Modulation of the brain N-glycoprofile was observed in a dose-dependent manner, mainly in the core-fucosylated glycans. The alterations observed were amplified using a collagen hydrogel as the mode of delivery. Consequently, this research demonstrated the capacity to administer CDNF to the brain via a biomaterial system and its influence on transforming the N-glycomic signature from a diseased state to a healthier one.