# Nanocarriers-Assisted Nose-to-Brain Delivery of Levodopa: Current Progress and Prospects
## 1 Introduction  
The first recognition of Parkinson's Disease (PD) is to be found in the scientific report of Dr. [PERSON] (\"Essay on the Trembling Paralysis\" from 1817) who defines the bradykinesia and the mask-like, stooped appearance, as neurological symptoms of a new, unclassified neurodegenerative disease. Nowadays, being the second most frequent chronic neurodegenerative disorder after Alzheimer's disease, PD threatens to progress into a latent pandemic and has doubled its prevalence over the past 25 years. Alarming global trends are the significant increases in PD-related deaths and disability-adjusted life years (DALYs) [1, 2, 3, 4].  
PD is considered a primarily idiopathic disease (in about 90% of the cases) with a multifactorial etiology in which environmental and/or genetic components (in about the rest 10% of the cases) are involved [5]. The main neuropathological finding characterizing PD is the massive deficit of dopaminergic neurons in substantia nigra; the pathogenesis includes misfolding, aggregation, and increased neurotoxicity of the \(\alpha\)-synuclein protein; subsequent mitochondrial dysfunction, ineffectiveness of the protein clearance systems (i.e., the ubiquitin-proteasome system and the autophagy-lysosome pathway), and neuroinflammation are reported [6, 7, 8, 9, 10]. Symptomatically, the impaired nigrostriatal dopaminergic innervation causes motor dysfunction--bradykinesia, loss of balance and gait stability, stiffness, and tremors. Non-motor symptoms, such as pain, fatigue, insomnia, depression, constipation,orthostatic hypotension, and others, are also known to play a role in the reduced quality of life (QoL) of patients [11; 12; 13; 14; 15]. With age being the foremost risk factor, PD's prevalence increases among individuals over 50 years old and is most prevalent in the elderly over 80 years old (1-3%); younger individuals aged 65-69 are substantially less affected (0.5-1%) [5].  
Despite the numerous studies on the etiology, pathogenesis, and pharmacotherapy of PD, long-term treatment with explicit efficacy and safety has not been yet established [16]. The current therapeutic strategy is limited to temporary suppression of the motor and non-motor symptoms by dopamine precursors, dopaminergic drugs, and deep brain stimulation [17; 18; 19; 20]. A gold standard, the most efficient and best tolerated symptomatic treatment of PD remains the oral administration of L-DOPA (a prodrug and dopamine precursor) in combination with the peripheral decarboxylase inhibitor carbidopa [21]. Major drawbacks of the conventional PD treatment with L-DOPA are the low systemic and brain bioavailability upon oral intake, the need for high doses, and the long-term use-associated peripheral complications mediated by dopamine [22]. The need exists for more efficient, cost-effective, and safe therapy; therefore, huge scientific resources have been directed towards the research and development of new alternatives for PD treatment. This article focuses particularly on the current progress in the nanocarriers-assisted nose-to-brain delivery of L-DOPA.  
The constant evolution of nanotechnologies reveals new opportunities in drug delivery and allows numerous advantages of the PD therapy. Generally, the drug loading into nanocarriers aims at increased chemical stability, modified release pattern, improved pharmacokinetics, targeted therapeutic action, selectivity, facilitated drug permeation, and lowered toxicity [23]. Specifically, the nose-to-brain drug delivery benefits from nanomaterials that can ensure prolonged mucosal retention, active or passive olfactory targeting, reduced cilia irritation, in situ phase transition, or enhanced drug penetrability. Mostly polymer-based or hybrid nanotechnologies fulfill the requirements of this delivery route, as well as the L-DOPA physicochemical peculiars [24]. Undoubtedly, the key to their successful clinical implementation lies in the production technology's simplicity, reproducibility, eco-friendliness, and toxicity concerns.