**1. Introduction**

Neurodegenerative diseases (ND) cause progressive loss of brain functions and overlapping clinical syndromes. Among the many risk factors associated with neurodegeneration, the aging process itself has by far the most impact. However, other environmental and genetic aspects are associated with the risk of suffering these diseases. Indeed, the NDs are the result of a combination of different environmental risk factors, such as vascular risk, tobacco consumption, alcohol and aging, together with different genes involved in the development of these central nervous system (CNS) disorders. For example, in Alzheimer's disease (AD), APOE4 (apolipoprotein E) is the major genetic risk factor. Moreover, mutations in APP, (amyloid precursor protein) PSEN1 (presenilin proteins) and PSEN2 probably accelerate the toxic accumulation of proteins that leads to the undergoing neurodegenerative process present in AD. Another example is mutation in GBA (glucocerebrosidase), which encodes β-glucocerebrosidase. Alterations in this gene lead to lysosomal enzyme deficiency and an increase in the prevalence of Parkinson diseases (PD). Other mutations in genes, such as LRRK2 (leucine-rich repeat kinase 2), parkin and SNCA, (alpha synuclein) which encodes the protein α-synuclein, are the most common causes of dominantly and recessively inherited PD. These NDs are age-dependent disorders that are becoming increasingly prevalent as life expectancy rises worldwide. This prevalence will increase, becoming a serious economic burden and public health problem. Despite AD and PD being the most common NDs, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia and the spinocerebellar ataxias are also examples of NDs, with aging as the main risk factor for all of them [1–3]. Although they have different clinical manifestations and symptoms, they share common features and mechanisms of neurodegeneration, highlighting protein deposits, mitochondrial homeostasis, stress granules and synaptic toxicity, together with a maladaptive innate immune response that converges in the form of chronic inflammation characterized by reactive gliosis and an increase in proinflammatory cytokines [4,5].

Despite the significant public health issues NDs have, to date, the treatments for these diseases remain symptomatic without halting the progression of the disease. Moreover, the lack of an overall positive effect on the clinical manifestation of the disease, together with the presence of systemic side effects, has prompted the patients to abandon their therapies [6,7]. Due to the lack of an effective treatment for NDs, in the last few years, promising new molecules, such as neurotrophic factors (NTFs), antioxidant molecules and polyunsaturated fatty acids (PUFAs), have been raised as a feasible therapeutic options to target the undergoing oxidative stress and inflammatory status or to enhance neurogenesis [8–10].

Nevertheless, no matter the treatment, one of the most challenging obstacles for an effective therapy for NDs is the low penetration efficiency of drugs to the CNS due to the presence of the blood brain barrier (BBB). In the last few years, different strategies have been developed in order to achieve brain targeting. These strategies include direct and indirect methods. The direct or invasive techniques include surgical methods to administer drugs directly into the brain and the disruption of the BBB to open it. Meanwhile, the indirect or noninvasive techniques include nonaggressive approaches to access the brain without affecting this barrier integrity [11,12]. These noninvasive techniques include alternative systemic administration routes like intranasal administration [13,14]. Gartziandia et al. conducted a study that successfully showed the brain delivery of therapeutics after intranasal administration with lipid nanoparticles coated with chitosan (CS) [15]. Moreover, the combination of the formulation with cell-penetrating peptides (CPP) has been disclosed as a useful strategy to enter the brain [16,17]. Anyway, one of the most studied approaches to attain this goal are nanotechnology-based drug delivery systems [18,19]. Among them, nanoparticles (NPs) have been widely used as a promising approach for ND treatment. NPs are highly stable 3D encapsulation systems that can be loaded with drugs and functionalized with targeting ligands or antibodies, and they can be used as nanocarriers to deliver drugs to the CNS [20]. Among other materials, natural or synthetic polymers and lipids have been employed in NP development [11].

Indeed, numerous research papers have combined NPs with well-known treatments or therapeutic approaches that have recently appeared, such as growth factors (GFs), antioxidant molecules and PUFAs entrapped in the nanoformulation [21–24]. All these research papers support the use of nanoparticles, offering many advantages over traditional formulations, such as protecting the molecule from degradation, increasing the half-life of the therapeutic molecules and, therefore, limiting multiple dosing and decreasing side effects. Among others, the nanostructured lipid carriers (NLCs) are an unstructured solid lipid matrix made of a mixture of blended solid and liquid lipids and an aqueous phase with a mixture of surfactants [25]. In addition, they have gained the attention of researchers since they exhibit a lack of toxicity, high drug loading capacity of both hydrophobic and hydrophilic compounds and a natural tendency to pass across the BBB [26]. Moreover, the NLCs can be functionalized with different substances to increase their tendency to pass through the BBB [27]. Examples of these molecules are chitosan (CS) and the cationic cell-penetrating peptide TAT; both molecules have increased brain targeting of therapeutic molecules for NDs treatment, as we pointed out in previous publications [15,24].

Up to today, most of the lipids used for NLC formulation are inert excipients, without any active role in preventing or treating diseases [28]. Indeed, only a few research groups have described the use of functional lipids that could play a therapeutic role in forming the lipid matrix, i.e., Ω-9 oleic acid incorporated into a NLC formulation for dermal applications [29]. Other kinds of functional lipids are PUFAs, Ω-3 and Ω-6 polyunsaturated fatty acids. As previously pointed out, PUFAs have been raised as a promising new approach to target neurodegenerative diseases. Although the biochemical mechanism undergoing the beneficial effect in NDs is not clear at all, they have exhibited the positive effect of decreasing the neuroinflammation process undergoing NDs, improving memory in animal models of AD, sensory motor tests in PD animal models and inhibiting amyloid-β fibrils both in vitro and in vivo [30–32]. Such functional lipids, which are also called nutraceutical, have proved to be a useful tool to manage NDs [33]; although they cannot totally restore brain functions, they may be beneficial to manage some symptoms of the disease or just as a coadjutant treatment. Actually, in the last few years, numerous observational studies showed an association between a diet rich in PUFAs and a lower risk of PD. Moreover, dietary treatments with PUFAs have shown to decrease the inflammatory status of these NDs and decrease depressive symptoms, among others [34–36].

Therefore, taking into account the promising results obtained with PUFAs in ND treatment, along with the beneficial effects of NLCs modified with CS and TAT for brain targeting, the objective of this research article is to combine both strategies for ND treatment. More concretely, the goal of the present work is to develop NLC with a functional lipid, such as DHA (docohexaenoic acid) and its hydroxylated derivate (DHAH), so the nanoparticles themselves could exhibit neuroprotective and antiinflammatory effects. In summary, we aim to demonstrate the beneficial effect of PUFAs incorporated to the NLC matrix, generating a new functional nanocarrier for entrapping different therapeutic molecules in the future and acting as a synergetic therapy.
