Search Results (1,990)

Central nervous system (CNS) inflammation and brain tumor treatment are constrained by the heterogeneity of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), as well as by the sequential barriers to drug delivery across lesions, target cells and subcellular organelles. Simply increasing brain exposure does not ensure that drugs reach their actual sites of action. This review systematically examines the pathological roles and therapeutic rationales of mitochondrial, lysosomal, nuclear, endoplasmic reticulum and Golgi apparatus dysfunction in neuroinflammation and glioblastoma within a two-stage delivery framework encompassing barrier crossing, lesion accumulation, cellular uptake and subcellular organelle localization. It also summarizes key design considerations for liposomes, polymeric nanoparticles, biomimetic membrane-based carriers, exosome-like carriers and focused ultrasound-assisted delivery strategies. Furthermore, translational bottlenecks are discussed, including BBB/BBTB heterogeneity, endosomal/lysosomal escape, organelle off-targeting, long-term safety and the extrapolation of preclinical models. Finally, personalized delivery designs guided by cascade targeting, dynamic visualization-based validation and disease stratification are proposed to support precise treatment of CNS inflammation and brain tumors. Full article

Background: Glioblastoma (GBM) is a primary malignant tumor of the central nervous system and has a high lethal rate despite therapeutic advances. Although immunotherapies have achieved great success in solid tumors, the highly immunosuppressive tumor microenvironment and the blood–brain barrier (BBB) obstruction hinder the development of immunotherapies for GBM. In this study, we innovatively developed a nanohydrogel composite vaccine (nanoCOM-GEL) for GBM immunotherapy via intranasal immunization. Methods: The nanoCOM-GEL used GelMA as the hydrogel matrix and was co-formulated with antigenic peptides, the BBB-penetrating peptide (peptide 22), as well as immune cell stimulants and chemokines. The efficiency of this vaccine in bypassing the BBB and its capacity to induce anti-GBM immune responses were evaluated in vitro and in vivo. Results: The nanoCOM-GEL vaccine demonstrated superior BBB-bypassing and BBTB-penetrating capabilities, potent immunostimulatory activity, and effective GBM-targeting efficacy, as validated in both cellular and animal models. In an orthotopic GBM mouse model (n = 8 per group), intranasal immunization with nanoCOM-GEL significantly extended median survival from 21 days (control group) to more than 60 days (nanoCOM-GEL group), representing a 2.8-fold increase (p < 0.001). The vaccine markedly inhibited tumor growth, as evidenced by an 82.5% reduction in tumor tissue at day 21 compared to controls (p < 0.01). Mechanistically, nanoCOM-GEL increased intratumoral CD8⁺ T cell infiltration by 9.5-fold and upregulated DCs by 6.4-fold, while simultaneously reducing intratumoral M2-type tumor-associated macrophages by 79.3% (p < 0.001), effectively reshaping the immunosuppressive tumor microenvironment. Conclusions: This innovative nanoCOM-GEL vaccine achieved potent anti-GBM therapeutic efficacy and provided a promising strategy for effective GBM immunotherapies. Full article

Streptococcus suis (S. suis) is a zoonotic pathogen capable of causing meningitis and other diseases. However, the molecular mechanisms underlying its ability to cross the blood brain barrier (BBB) and invade the central nervous system remain incompletely understood. In this study, non-targeted metabolomics was used to investigate the effects of S. suis type 2 strain HA9801 infection on the metabolic profile of human brain microvascular endothelial cells (hBMECs), and to examine associations between key metabolites and BBB permeability. The results showed that HA9801 infection induced changes in the metabolic profile of hBMECs, with significant enrichment of the histidine metabolism pathway. Notably, several histamine-related metabolites were altered. Changes in HDC and HNMT gene expression, together with alterations in histamine-related metabolites detected by non-targeted metabolomics, were consistent with changes in histamine-related metabolism. These observed metabolic alterations were accompanied by significant accumulation of endogenous histamine, which was accompanied by reduced expression of tight junction protein genes (TJP1, OCLN, and CLDN5) and increased BBB permeability. Moreover, elevated histamine levels were associated with increased invasion and translocation of S. suis across the BBB. This study suggests that S. suis impairs BBB integrity in association with alterations in the host histidine–histamine metabolic axis, which were accompanied by increased histamine levels, reduced expression of tight junction protein genes, and enhanced bacterial invasion and translocation. These findings identify histamine-associated signaling as a potential pathway for further investigation in S. suis-associated BBB dysfunction. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. Current therapeutic approaches are still limited due to the complexity and heterogeneity of these diseases, which points toward an urgent need to discover and develop new therapeutic agents. Natural compounds are a promising source of novel bioactive agents targeting multiple mechanisms of action implicated in neurodegeneration. Andrographolide (ANDRO) is a natural compound extracted from Andrographis paniculata, a traditional Chinese herb known for its anti-inflammatory and antioxidant properties, which has emerged as a potential neuroprotective agent due to its ability to cross the blood–brain barrier (BBB). ANDRO can exert neuroprotective effects by modulating numerous transcription factors and signaling pathways across different cell types in the central nervous system (CNS). It has been described that ANDRO reverses cognitive and/or motor impairments in AD and PD study models. However, the cellular and molecular mechanisms behind these protective effects are still being elucidated. In this review, we analyze the most recent findings on ANDRO, a neuroprotective agent with multiple biological targets that could reduce the progression of the most prevalent neurodegenerative diseases, AD and PD. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor with limited therapeutic options due to its invasive nature, therapeutic resistance, and the challenge of drug delivery across the blood–brain barrier (BBB). Mesenchymal stem cells (MSCs), owing to their tumor tropic properties and ability to cross the BBB, offer a promising platform for targeted anti-cancer delivery. We previously engineered MSCs to express CD::UPRT and TRAIL, along with chemokine receptors to enhance tumor homing (MSC-CD-TRAIL; BM03). This study evaluated the anti-tumor efficacy of BM03 using GBM patient-derived organoids (GBOs), clinically relevant in vitro models. Using a GBO–MSC co-culture system, BM03 significantly increased cell death and reduced viability in GBOs from four GBM patients compared with controls and MSC-WT groups. In 3D invasion assays, BM03-treated GBOs showed markedly reduced invasive outgrowth, accompanied by downregulation of EMT markers (Zeb1 and Snail) and stem-like markers (Olig2 and Sox2), particularly in invasive regions. GFAP expression remained unchanged, suggesting selective targeting of tumor stem-like cells. Live-cell imaging further demonstrated BM03 infiltration into GBOs, which was associated with increased apoptosis, as evidenced by elevated cleaved caspase-3 levels. These findings provide organoid-based preclinical evidence supporting further evaluation of BM03 as an MSC-based therapeutic strategy for GBM. Full article

Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent/metabolite pharmacokinetics, blood–brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation and experimental modulation of α-synuclein; support for AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial protection, nuclear factor-kappa B (NF-κB)-related inflammation, and amyloid-β (Aβ) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin–proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer’s disease (AD), Parkinson’s disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose–response, and efficacy require adequately powered disease-specific trials. Full article

The fact that the population is getting older has greatly increased the occurrence of cognitive decline and neurodegenerative diseases, underlining the importance of having reliable biomarkers that can measure biological aging before irreversible neurological damage takes place. New evidence shows that brain aging is not just the result of changes within neurons themselves but is also greatly affected by the gut microbiota via immune, metabolic, endocrine, and neurovascular signaling. This review brings together the existing knowledge about biomarkers of biological aging-such as telomere shortening, epigenetic clocks, oxidative stress, inflammation, cellular senescence, and metabolic dysfunction-as well as established cognitive biomarkers obtained from neuroimaging, cerebrospinal fluid, blood, genetic evaluations, and neuropsychological tests. We also point out that changes associated with age in the composition of the gut microbiota and the metabolites it produces are becoming more and more involved in the mechanisms connecting intestinal dysbiosis, dysfunction of the blood-brain barrier (BBB), neuroinflammation, and age-related cognitive decline. Through this approach of combined and complementary biomarker systems, we hypothesize that the gut microbiota has emerged as a central regulator of biological and cognitive aging and may provide a useful source for development of biomarkers of cognitive resilience and risk of neurodegenerative diseases. Lastly, we consider microbiome-based interventions, including probiotics, prebiotics, dietary changes, fecal microbial transplant, and new treatment modalities derived from molecular studies, as possible approaches to the prevention and management of age-related cognitive decline. Collectively, this review provides a comprehensive framework linking aging biology, microbiome science, and cognitive biomarkers to advance biomarker-driven precision medicine for healthy brain aging. Full article

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by impaired social interaction and repetitive stereotyped behaviors, with pathogenic mechanisms that remain incompletely understood. The gut microbiota has emerged as a key regulator of ASD; however, its impact on hippocampal proteomic and phosphoproteomic signatures has not been fully characterized. In this study, we performed fecal microbiota transplantation (FMT) by transferring fecal samples from children with ASD and typically developing controls into antibiotic-treated mice. Gut microbiota from children with ASD induced several ASD-like behaviors in recipient mice, accompanied by aberrant activation of microglia, astrocytes, and neurons, as well as impaired neurogenesis. Phosphoproteomic profiling combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that differentially phosphorylated proteins were predominantly enriched in synapse-related pathways. ASD-derived microbiota markedly reduced synaptic density, downregulated the synaptic proteins SYP and PSD-95, and inhibited the expression of blood–brain barrier (BBB) tight junction proteins. In silico structural simulations using AlphaFold3 (AF3) and HADDOCK further supported that ASD-FMT may promote abnormal phosphorylation, potentially remodeling SHANK3 and SRRM2 conformations and weakening the binding affinity of SHANK3. Integrative proteomic and phosphoproteomic screening identified FNDC3A as a potential susceptibility-associated protein upregulated by gut microbiota from children with ASD, which was verified in mouse hippocampal tissues and plasma samples from children with ASD using Western blotting and ELISA, respectively. Mechanistically, ASD pathogenesis may be attributable not only to the dysregulation of classical ASD susceptibility genes but also to gut microbiota-driven post-translational phosphorylation remodeling of multiple protein structures. Importantly, this study established an innovative research framework that integrates in silico analyses with wet-lab experiments, yielding novel insights into ASD pathogenesis from the perspective of gut microbiota-induced alterations in the hippocampal phosphoproteome and revealing a plausible molecular mechanism underlying ASD. Full article

Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, which remains difficult to treat because of extensive intratumoral heterogeneity, intrinsic and acquired treatment resistance, a profoundly immunosuppressive tumor microenvironment (TME), and restricted drug delivery across the blood–brain barrier (BBB). Owing to their relatively low molecular mass, potential for BBB penetration, and ability to modulate multiple targets, natural and synthetic compounds have attracted increasing interest as candidates for GBM treatment. This narrative review summarizes the mechanisms by which naturally derived compounds—including saponins, flavonoids, and sesquiterpene lactones—and synthetic small molecules exert anti-GBM effects on tumor and the TME. Their reported actions include suppressing key prosurvival pathways, such as the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa B (NF-κB), and mutant p53 signaling; activating regulated cell-death processes, including apoptosis, pyroptosis, and parthanatos, as well as autophagy-associated cell death; and remodeling the tumor immune milieu to promote CD8⁺ T-cell infiltration. In preclinical models, some of these agents also overcome temozolomide (TMZ) resistance and resensitize glioma stem cells (GSCs) to chemotherapy or radiotherapy. Future studies should prioritize molecularly informed patient stratification, rational combination strategies, and advanced nanocarrier-mediated delivery platforms to facilitate the clinical translation of small-molecule therapeutics for GBM. Full article

The neurovascular unit (NVU) is composed of a diverse array of cells and an extracellular matrix (ECM). Neural cells and blood vessels are intricately interconnected, forming a cohesive whole. Specific cellular components and structures within the NVU play an indispensable role in maintaining homeostasis of the central nervous system (CNS). With the advancement and maturation of cell co-culture technology, various three-dimensional (3D) NVU models continue to emerge, offering a more objective and comprehensive perspective for in vitro studies of CNS diseases. Specifically, these 3D NVU models include Transwell Chamber models, gel-polydimethylsiloxane (PDMS)-based 3D models, self-assembled NVU models and microfluidic NVU models, which reconstruct the complex NVU architecture to varying degrees. This review systematically summarizes multiple 3D construction strategies for in vitro NVU to overcome the limitations of conventional cellular tests or animal experiments, highlights the critical roles of biomimetic gel in recapitulating native cell-gel crosstalk, comparatively analyzes four major 3D NVU technical routes in terms of cellular composition, vascular morphology, barrier performance, and reproducibility, categorizes application scenarios of 3D NVU platforms oriented to practical research demands, including oxygen-glucose deprivation/reoxygenation (OGD/R) injury modeling, blood-brain barrier (BBB) permeability assay, CNS drug penetration screening, neuroinflammation and neurotoxicity evaluation, proposes practical principles for model selection under different experimental purposes, and concludes with current bottlenecks, including imperfect vascular network maturation and lack of unified evaluation criteria, together with future perspectives for standardized 3D NVU in vitro. By comparing the advantages and limitations of these approaches, we aim to clarify their optimal applicability for investigating specific pathological mechanisms and screening potential therapeutics. Full article

Although the Pacific oyster (Crassostrea gigas) is a premium marine protein source, its neuroprotective peptidome remains largely uncharacterized. This study established an integrated in silico and in vitro pipeline to discover acetylcholinesterase (AChE)-targeting peptides with cellular AChE-regulating and neuroprotective peptides from simulated gastrointestinal digests of oyster. Peptidomic profiling identified 18,292 sequences, which were filtered down to seven candidates predicted to have favorable blood–brain barrier (BBB) permeability and to be non-toxic and non-allergenic (VPYPR, VPVHF, HHTF, PVHF, GPKPW, HWF, and KYW) via multi-step virtual screening. In cellular assays, simulated H₂O₂ injury (500 μM) reduced PC12 cell viability to 47.53 ± 4.53%. Compared with the model group, pretreatment with the three most potent candidates—HHTF, VPYPR, and VPVHF (200 μM)—significantly rescued injured cells, restoring cell viability to 88.31 ± 7.83%, 85.12 ± 3.35%, and 82.00 ± 3.47%, respectively (p < 0.05). These peptides effectively fortified cellular antioxidant defenses by increasing glutathione (GSH) levels to 24.24, 30.11, and 26.83 nmol/mg protein (from 20.22 nmol/mg protein in the model group) and superoxide dismutase (SOD) activity to 151.41, 153.97, and 151.96 U/mg protein (from 119.33 U/mg protein), while suppressing malondialdehyde (MDA) accumulation to 0.088, 0.064, and 0.086 nmol/mg protein (from 0.193 nmol/mg protein). Crucially, the peptides alleviated cholinergic dysfunction by normalizing the H₂O₂-induced elevation of intracellular AChE activity (11.39 nmol/min/mg protein) down to 7.02, 6.22, and 7.14 nmol/min/mg protein, respectively. Specifically, VPYPR (200 μM) restored AChE activity to a level (6.22 nmol/min/mg protein) that was not significantly different from that in the normal control group (p > 0.05). Molecular dynamics (MD) simulations (100 ns) and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations identified VPYPR as the leading candidate with a remarkably low binding free energy of −49.74 ± 3.58 kcal/mol. This study demonstrates that oyster gastrointestinal digests are valuable reservoirs of multi-target neuroprotective ingredients and provides an efficient strategy for marine bioactive peptide discovery. Full article

In vitro neurovascular unit (NVU) models are essential for reproducing blood–brain barrier (BBB) transport and neurovascular cell interactions. However, the literature remains fragmented: biomaterial chemistry, fabrication parameters and organ-on-a-chip architecture are commonly evaluated in isolation, while inconsistent reporting of matrix properties, processing history, cell source, flow and barrier readouts prevents head-to-head comparison and the extraction of transferable design rules. To address this gap, this review integrates biomaterials, manufacturing technologies and organ-on-a-chip engineering within a unified material–process–structure–function framework. We translate endothelial junctions, basement-membrane components and perivascular cells into experimentally actionable material requirements; compare natural, synthetic, semisynthetic and decellularized extracellular-matrix hydrogels; and examine crosslinking, peptide functionalization, stimuli responsiveness, composite-network formation and preparation methods. Findings from Transwell, microfluidic, tubular, self-assembled and 3D-bioprinted BBB systems are used to relate matrix stiffness, degradability, ligand density, permeability, device-body material and fabrication route to barrier maturation, analytical access and reproducibility. By defining matched controls and minimum reporting requirements for chemistry, mechanics, transport and processing, this review provides a practical basis for next-generation BBB models that can improve permeability and efficacy screening in drug discovery, reproduce disease- and patient-specific barrier dysfunction, and support individualized response testing with iPSC- or patient-derived cells. Full article

Background/Objectives: Blood–brain barrier (BBB) permeability is a major practical obstacle in central nervous system (CNS) drug discovery, because only a small fraction of drug-like molecules achieve sufficient brain exposure. Methods: We present DeepBBB, a graph-based, data-composition-aware screening workflow for predicting BBB permeability and for constructing BBB-focused screening libraries from commercial chemical space. Rather than introducing a new graph-learning architecture, the workflow combines standard graph convolutional and graph-transformer models with deliberate control of training-set composition, commercial-library filtering, chemical-space profiling, and prospective experimental evaluation. Three model variants were trained on the Blood–Brain Barrier Database (B3DB): a baseline classifier/regressor pair (DeepBBB_V1_BC/RG), a variant trained with a more strongly negative-enriched configuration (DeepBBB_V2_BC), and a graph-transformer counterpart (DeepBBB_trans_BC/RG). Because the sample-level split assignments and per-compound predictions from the original runs were not recoverable, the archived summary metrics are reported descriptively in the main text and are not used to support calibration, scaffold-level validity, or generalization. Applying the workflow to the ChemDiv collection (~1.5 million compounds) and the Enamine REAL lead-like space (~1.7 billion compounds) produced three progressively more stringently filtered BBB-focused libraries (21,991; 4,808,885; and 151,790 compounds). Results: Analysis of available processed data indicated that the predicted BBB-permeable set occupies a compact, BBB-compatible property region. Physicochemical, fragment, and scaffold summaries were interpreted descriptively at the constructed-library level. In a first prospective campaign, one of 12 tested candidate compounds was PAMPA-BBB-positive (all-tested molecular-level positive fraction 8.3%; exact 95% CI 0.2–38.5%). In a second campaign, five of 35 tested candidate compounds were PAMPA-BBB-positive (14.3%; exact 95% CI 4.8–30.3%); 13 compounds were not quantifiable and were not treated as ordinary CNS-negative measurements, and the two campaigns differed in compound source, selection strategy, and assay setting, so the numerical difference is reported descriptively rather than causally. Conclusions: Together, these results support the feasibility of BBB-focused computational filtering and a PAMPA-BBB evaluation workflow for CNS-oriented discovery. Full article

Background/Objectives: The aim of the present study was to investigate the mechanisms in Parkinson’s disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, aggregation of α-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, gut dysbiosis, and blood–brain barrier (BBB) impairment. Although there are several approved therapies that have been developed, their aqueous solubility, oral bioavailability, first-pass metabolism, and inability to penetrate the BBB make them less effective over time. This review is intended to critically analyze the potential of self-nanoemulsifying drug delivery systems (SNEDDSs) as a pathogenesis-related approach to enhance the delivery and therapeutic activity of repurposed drugs and conventional drugs for PD. Methods: A comprehensive literature search was conducted to address the pathogenic mechanisms of PD, the deficiencies of current pharmacotherapy, recent developments in SNEDDS formulation strategies and their application in improving oral bioavailability, lymphatic transport, BBB penetration and targeted brain delivery. A special focus was dedicated to drug repurposing, functionalized SNEDDSs, PEGylation, and gut–brain axis modulation. Results: SNEDDSs significantly enhance the water solubility, stability, intestinal absorption and systemic exposure of poorly water-soluble therapeutic agents and, to a certain extent, lymphatic uptake to avoid first-pass metabolism. These systems include improved brain delivery, decreased pharmacokinetic variability, and prolonged drug levels within the therapeutic range. Moreover, SNEDDSs can be used to deliver multiple molecules that are found to be neuroprotective, antioxidant, anti-inflammatory and probiotic, all at once, which can act on multiple pathogenic mechanisms associated with PD. Functionalized and PEGylated SNEDDSs add further to formulation stability, extend systemic circulation and increase efficiency of brain targeting. Conclusions: SNEDDSs are a promising translational nanomedicine platform for enhancing the effectiveness of conventional and repurposed therapeutics in PD, which address key pharmacokinetic and biological challenges. The next generation of oral therapies with targeted surface engineering, precision drug repurposing and clinical validation will be expected to bring about a faster advancement of drugs that can alter the course of disease rather than giving only symptomatic relief. Full article