An injectable nanoreinforced hydrogel for combined GDNF-loaded nanoparticles and mesenchymal stem cell therapy in Parkinson's disease.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, and no current treatment can halt neurodegeneration or restore the nigrostriatal pathway. Although glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) hold promise as disease-modifying strategies, their clinical translation is limited by major delivery challenges, including poor tissue distribution, limited protein stability, and low cell survival after transplantation. Here, we present an injectable supramolecular hyaluronic acid-based hydrogel for the combined delivery of GDNF-loaded nanoparticles and MSCs, enabling sustained neurotrophic factor release and providing a supportive microenvironment for cell therapy. The formulation showed good in vivo biocompatibility after intrastriatal injection in healthy rats. The therapeutic performance of the system was evaluated in two complementary animal models of PD. In a unilateral intrastriatal 6-hydroxydopamine rat model, this neurorestorative treatment paradigm produced significant and sustained motor improvement despite the absence of histological recovery of the nigrostriatal pathway. In contrast, in a neuromelanin-producing mouse model, this neuroprotective strategy prevented motor deterioration and preserved both tyrosine hydroxylase-positive neurons in the substantia nigra and dopaminergic striatal innervation, while reducing the number of microglia in the substantia nigra. Together, these results demonstrate that the dual delivery of GDNF and MSCs within an injectable hydrogel can provide functional benefit in PD across different pathological contexts, highlighting the critical importance of treatment timing, disease stage, and the underlying neuroinflammatory environment.