Mitochondria-targeted delivery of bromocriptine via cerium vanadate nanocarriers for Parkinson's disease

Parkinson's disease (PD) is a therapeutically challenging neurodegenerative disease marked by profound disruptions in mitochondrial-redox axis. Current therapeutic agents such as Bromocriptine mesylate (BM) exhibit neuroprotective potential, however their clinical benefit remains largely symptomatic as they do not address the underlying cause of neurodegeneration. Moreover, the therapeutic efficacy of BM is compromised due to its poor solubility, low bioavailability, and inadequate brain penetration. To overcome these biological barriers and provide mechanistic interventions, we report the first drug-loaded porous cerium vanadate nanoplatform (MT-BM-CNP), in which BM, as a model drug is encapsulated within cerium vanadate nanoparticles and surface-functionalized with L-methyl ester tryptophan-conjugated triphenylphosphonium for mitochondrial targeting. The intrinsic Ce³⁺/Ce⁴⁺ and V⁴⁺/V⁵⁺ redox-switching of cerium vanadate provides strong antioxidant buffering, while the triphenylphosphonium moiety facilitates selective mitochondrial delivery, a central locus of PD pathology. The MT-BM-CNP complex illustrates higher neuroprotective potential by integrating dopaminergic stimulation with intrinsic redox regulation, while exhibiting enhanced stability and sustained drug release. In the preclinical 6-hydroxydopamine PD models, the nanoformulation preserved nigral dopaminergic neurons, restored dopamine levels and significantly improved motor function, with preferential protection of neuronal somata over striatal axon terminals. This study introduces a novel drug-loading strategy using porous cerium vanadate nanoparticles and establishes MT-BM-CNP as a novel mitochondrial-redox axis targeted therapeutic system. This strategy is a significant advancement in nanotechnology-mediated neuroprotection for PD offering not only symptomatic relief but disease-modifying potential as well.