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Pharmaceutics
Special Issues
Targeted Therapies and Drug Delivery for Neurodegenerative Diseases
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Targeted Therapies and Drug Delivery for Neurodegenerative Diseases

A Special Issue of Pharmaceutics (ISSN 1999-4923) belonging to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 20 October 2026 | Viewed by 17863

Editors

Dr. Ramona Meanti

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: neurodegenerative diseases; pharmacology; drug discovery; drug repurposing; neuroinflammation
Special Issues, Collections and Topics in MDPI journals
Dr. Chiara Lucchi

E-Mail Website
Guest Editor
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy
Interests: neurodegenerative disease; epilepsy; pharmacology; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The treatment of neurodegenerative diseases faces two major hurdles: the complexity of disease mechanisms and the challenge of efficiently delivering therapeutics to the central nervous system. Disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and epilepsy involve intricate pathological cascades, including protein misfolding, neuroinflammation, oxidative stress, and synaptic dysfunction. Moreover, the blood–brain barrier (BBB) severely limits the passage of most pharmacological agents, hindering the efficacy of potential treatments.

Recent breakthroughs in targeted therapies and advanced drug delivery systems are reshaping the therapeutic landscape, offering unprecedented precision in modulating pathological processes while overcoming biological barriers. Nanoparticle-based carriers, ligand-directed approaches, exosome-mediated delivery, and biomimetic platforms have shown great promise in enhancing drug bioavailability and selectivity. In parallel, gene- and peptide-based therapeutics are emerging as powerful tools to correct disease mechanisms at the molecular level, paving the way for disease-modifying treatments.

This Special Issue seeks cutting-edge contributions on innovative strategies that push the boundaries of neurodegenerative disease treatment. We invite original research and review articles focusing on novel drug formulations, advanced delivery platforms, and BBB-targeting mechanisms and translational studies bridging preclinical and clinical applications. By fostering interdisciplinary collaboration and highlighting the latest advancements in the field, this issue aims to accelerate the development of transformative therapies and improve patient outcomes in the fight against neurodegeneration.

We look forward to receiving your contributions.

Dr. Ramona Meanti
Dr. Chiara Lucchi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • targeted drug delivery
  • blood–brain barrier
  • neurodegenerative disease treatment
  • precision medicine
  • neuroscience

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Published Papers (7 papers)

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Research

Jump to: Review

18 pages, 8018 KB  
Article
Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons
by Mohamed Aghyad Al Kabbani, Laura Köhler, Tamara Wied, Daniel Adam, Jennifer Klimek and Hans Zempel
Pharmaceutics 2026, 18(8), 1038; https://doi.org/10.3390/pharmaceutics18081038 - 20 Aug 2026
Viewed by 541
Abstract
Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer’s disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment (‘TAU missorting’), dissociates from microtubules, [...] Read more.
Background: Microtubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by posttranslational modifications (PTMs) such as polyglutamylation. In Alzheimer’s disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment (‘TAU missorting’), dissociates from microtubules, aggregates into neurofibrillary tangles, and contributes to microtubule destabilization and neuronal death. Objectives and Methods: Here, we investigated the role of tubulin tyrosine ligase-like proteins (TTLLs) in TAU missorting and microtubule dysregulation using human-induced pluripotent stem cell (hiPSC)-derived cortical neurons treated with oligomeric amyloid-beta (oAβ) to replicate AD-like conditions. TTLL1, TTLL4, and TTLL6 were selectively knocked down (KD) to assess their impact on TAU missorting and microtubule stability. Fluorescence resonance energy transfer (FRET) microscopy was used to examine proximities between TAU and TTLL proteins. Results: We observed TAU missorting, increased tubulin polyglutamylation, decreased tubulin acetylation associated with microtubule destabilization, and synaptic declustering in oAβ-treated neurons. TTLL1 KD significantly reduced TAU missorting, tubulin polyglutamylation, and synaptic disintegration, while TTLL4 KD showed moderate effects, and TTLL6 KD restored microtubule acetylation. Importantly, TTLL KD did not impair neuritic networks, dendritic complexity, or neuronal activity. FRET microscopy in HEK293T cells revealed a close molecular proximity between TAU and TTLL1 consistent with a potential direct or complex-mediated association, but not with other TTLLs, suggesting a direct role of TTLL1 in TAU-mediated toxicity. Conclusions: Our findings identify TTLL1 as a promising therapeutic target for limiting TAU-associated cytoskeletal pathology in AD. These results support further development of pharmacological or genetic strategies targeting TTLL1 as a disease-modifying approach for AD and related tauopathies. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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23 pages, 2451 KB  
Article
Phenylephrine per se or Combined with Pregabalin Ameliorates Mononeuropathic Pain in Rats
by Sarah Kadhim Abbood, Nariman Essmat, Imre Boldizsár, Jr., Judit Mária Kirchlechner-Farkas, Csenger Kovácsházi, Yashar Chalabiani, Kornél Király, Ildikó Miklya, Zoltán Giricz, Laszlo G. Harsing, Jr., E. Sylvester Vizi and Mahmoud Al-Khrasani
Pharmaceutics 2026, 18(3), 334; https://doi.org/10.3390/pharmaceutics18030334 - 8 Mar 2026
Cited by 1 | Viewed by 1618
Abstract
Background/Objectives: Neuropathic pain (NP) affects approximately 6.9–10% of the population and is inadequately managed by the current therapies, as reflected by a high number needed to treat (NNT). These data highlight the socio-economic burden of NP on healthcare. Thus, the repurposing of existing [...] Read more.
Background/Objectives: Neuropathic pain (NP) affects approximately 6.9–10% of the population and is inadequately managed by the current therapies, as reflected by a high number needed to treat (NNT). These data highlight the socio-economic burden of NP on healthcare. Thus, the repurposing of existing medications and new drug combinations to enhance therapeutic efficacy are required. Methods/Results: Here, we show that intrathecal phenylephrine (PE) in a dose of 3, 10, or 30 nmol/rat acutely alleviates tactile allodynia in rats with mononeuropathic pain evoked by partial sciatic nerve ligation. Prazosin and idazoxan, which are considered as selective α1- and α2-adrenoreceptor antagonists, respectively, reversed the antiallodynic effects of PE. In ex vivo experiments, PE induced a significant cytosolic [3H]-noradrenaline release from mouse spinal tissue. In addition, in the mouse vas deferens, PE produced smooth muscle contraction in prazosin and idazoxan sensitive manner. As a novelty, in another set of experiments, oral PE (5 mg/kg) and pregabalin (PGB, 25 mg/kg) combination, but not the individual drug treatments, acutely alleviated allodynia in rats with mononeuropathy. In addition, the antiallodynic action of the combination was further enhanced upon chronic treatment. Under isoflurane anesthesia, this combination was devoid of cardiovascular side effects attributed to systolic and diastolic blood pressure, mean arterial pressure, or heart rate. PGB induced motor dysfunction was not altered upon the combination with PE. Conclusions: These data suggest that PE in combination with PGB shows promise in preclinical settings; however, the necessity for further studies is paramount to detail the pharmacokinetic interactions involved. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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15 pages, 2559 KB  
Article
2,3,4-Trihydroxybenzophenone Disassembles Amyloid β Aggregates and Ameliorates Synaptic Deficits
by Eunbi Cho, Kumju Youn, Huiyoung Kwon, Ho Jung Bae, Minho Moon, Mira Jun and Dong Hyun Kim
Pharmaceutics 2026, 18(3), 320; https://doi.org/10.3390/pharmaceutics18030320 - 2 Mar 2026
Viewed by 1463
Abstract
Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which no disease-modifying therapy that halts or substantially slows disease progression is currently available. Although antibody therapies targeting amyloid β (Aβ) have recently received FDA approval, their high cost, limited efficacy, and [...] Read more.
Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which no disease-modifying therapy that halts or substantially slows disease progression is currently available. Although antibody therapies targeting amyloid β (Aβ) have recently received FDA approval, their high cost, limited efficacy, and potential adverse effects highlight the need for alternative solutions. Therefore, the development of low-molecular-weight compounds capable of reducing toxic Aβ aggregates is of considerable interest. In this study, we investigated the effects of 2,3,4-trihydroxybenzophenone (THB) on the inhibition and disassembly of Aβ1–42 aggregates through in vitro and in vivo experiments. Methods: In vitro assays were performed to evaluate the effects of THB on Aβ1–42 aggregation and fibril disassembly. Cell viability assays and hippocampal slice electrophysiology were conducted to assess neurotoxicity and synaptic function. In vivo effects were examined in Aβ1–42 aggregate-injected mice and in 5 Familial AD mutations (5XFAD) mice using behavioral, histological, and electrophysiological analyses. Results: THB inhibited Aβ1–42 aggregation in a concentration-dependent manner and promoted the disassembly of preformed fibrils. THB attenuated Aβ1–42-induced Neuro2a cell death and restored Aβ1–42 aggregate-associated long-term potentiation (LTP) deficits in hippocampal slices. In Aβ1–42 aggregate-injected and 5XFAD mice, THB reduced amyloid pathology and neuroinflammatory markers and improved synaptic function and memory performance. Conclusions: These findings suggest that THB modulates pathogenic Aβ1–42 assemblies and provides a structural basis for the development of small-molecule modulators of Aβ1–42 aggregation with potential preventive or disease-modifying applications in AD. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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20 pages, 2458 KB  
Article
Impact of Neonatal Fc Receptor on Transferrin Receptor Antibody Fusion Protein Pharmacokinetics
by Adenike Oyegbesan, Nataraj Jagadeesan, Devaraj V. Chandrashekar and Rachita K. Sumbria
Pharmaceutics 2026, 18(2), 269; https://doi.org/10.3390/pharmaceutics18020269 - 22 Feb 2026
Cited by 1 | Viewed by 1850
Abstract
Background: Transferrin receptor-targeting monoclonal antibodies (TfRMAbs) enhance brain drug delivery by facilitating TfR-mediated transcytosis across the blood–brain barrier (BBB). Data suggest that chronic TfRMAb dosing reduces their plasma exposure in a dose- and fusion partner-dependent manner; however, the underlying mechanisms remain unclear. [...] Read more.
Background: Transferrin receptor-targeting monoclonal antibodies (TfRMAbs) enhance brain drug delivery by facilitating TfR-mediated transcytosis across the blood–brain barrier (BBB). Data suggest that chronic TfRMAb dosing reduces their plasma exposure in a dose- and fusion partner-dependent manner; however, the underlying mechanisms remain unclear. The neonatal Fc receptor (FcRn) extends IgG half-life via recycling, but its saturation after repeated doses may alter the pharmacokinetics (PK) of IgG fusion proteins. This study evaluated the role of the FcRn on the PK and biodistribution of TfRMAb fusion proteins. Methods: We examined TfRMAb alone and TfRMAb fused to erythropoietin (TfRMAb-EPO) or TNFα receptor (TfRMAb-TNFR) in wild-type (WT) and FcRn knockout (KO) mice following acute (single dose) or chronic (3× weekly for 4 weeks) subcutaneous administration at 3 mg/kg. Plasma levels, tissue biodistribution, and FcRn binding were measured using immunoassays. Results: Our results show that fusion partners influenced FcRn-mediated recycling and PK of TfRMAb fusion proteins. After acute dosing, TfRMAb-TNFR exhibited the greatest reduction in plasma exposure in FcRn KO versus WT mice, compared with TfRMAb and TfRMAb-EPO. Chronic dosing reduced the plasma persistence of all fusion proteins in WT mice. In FcRn KO mice, plasma exposure of TfRMAb and TfRMAb-EPO decreased with chronic dosing, whereas TfRMAb-TNFR showed no further reduction. Differences in FcRn binding affinity likely explain these patterns. Tissue distribution largely mirrored plasma concentrations. Conclusions: FcRn regulates plasma concentrations of TfRMAb fusion proteins in a fusion partner-dependent manner. While FcRn-mediated protection regulates plasma exposure with acute dosing, additional mechanisms beyond FcRn saturation appear to regulate plasma exposure during chronic dosing. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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Review

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25 pages, 1907 KB  
Review
Epilepsy as a Multiscale Network Disorder: Integrating Precision Therapeutics and Emerging Experimental Platforms
by Wonseok Chang, Amy Seomin Kwak, Seung Ho Han, Dae Yong Song, Hong Il Yoo and Jung Ho Lee
Pharmaceutics 2026, 18(8), 969; https://doi.org/10.3390/pharmaceutics18080969 - 7 Aug 2026
Viewed by 770
Abstract
Background/Objectives: Epilepsy remains a major neurological disorder, with approximately one-third of patients continuing to experience pharmacoresistant seizures despite the availability of numerous antiseizure medications (ASMs). While current therapies primarily target neuronal hyperexcitability through modulation of ion channels and neurotransmitter systems, increasing evidence [...] Read more.
Background/Objectives: Epilepsy remains a major neurological disorder, with approximately one-third of patients continuing to experience pharmacoresistant seizures despite the availability of numerous antiseizure medications (ASMs). While current therapies primarily target neuronal hyperexcitability through modulation of ion channels and neurotransmitter systems, increasing evidence suggests that epileptogenesis arises from multiscale interactions involving molecular, cellular, circuit, network, neuroinflammatory, and neurovascular mechanisms. Although therapeutic strategies have diversified, this expanded mechanistic understanding has not yet been fully incorporated into therapeutic development and evaluation. This review integrates current knowledge of multiscale epilepsy pathophysiology with recent therapeutic advances and emerging experimental platforms. Methods: This narrative review synthesized literature identified primarily through PubMed and Google Scholar searches through January 2026, supplemented by targeted updates of therapeutic development and regulatory status through July 2026. Particular emphasis was placed on ion channel modulators, synaptic and neuromodulatory therapies, neuroinflammatory interventions, precision genetic approaches, and human-relevant experimental platforms, including induced pluripotent stem cell (iPSC)-derived models, brain organoids, multi-electrode arrays (MEAs), organ-on-a-chip systems, multi-omics technologies, and artificial intelligence (AI)-based analytical frameworks. Results: Current and emerging therapies target increasingly diverse molecular, circuit, neuromodulatory, and neuroinflammatory mechanisms. However, drug resistance remains multifactorial, and the long-term effects of therapeutic interventions on network remodeling, neuro-glial interactions, and sustained clinical response remain incompletely understood. NAMs provide complementary capabilities for patient-specific disease modeling, functional network phenotyping, neurovascular modeling, and the integration of molecular, electrophysiological, and computational data across biological scales. Conclusions: Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability. The coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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27 pages, 1270 KB  
Review
Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain
by Jurga Bernatoniene, Dalia M. Kopustinskiene, Roberto Casale, Alessandro Medoro, Sergio Davinelli, Luciano Saso and Kestutis Petrikonis
Pharmaceutics 2026, 18(1), 118; https://doi.org/10.3390/pharmaceutics18010118 - 16 Jan 2026
Cited by 9 | Viewed by 2920
Abstract
This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing [...] Read more.
This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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24 pages, 580 KB  
Review
Overcoming the Blood–Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases
by Han-Mo Yang
Pharmaceutics 2025, 17(8), 1041; https://doi.org/10.3390/pharmaceutics17081041 - 11 Aug 2025
Cited by 60 | Viewed by 7790
Abstract
The increasing global health crisis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood–brain barrier (BBB), which prevents more [...] Read more.
The increasing global health crisis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood–brain barrier (BBB), which prevents more than 98% of small molecules and all biologics from entering the central nervous system. The therapeutic landscape for neurodegenerative diseases has recently undergone transformation through advances in targeted drug delivery that include ligand-decorated nanoparticles, bispecific antibody shuttles, focused ultrasound-mediated BBB modulation, intranasal exosomes, and mRNA lipid nanoparticles. This review provides an analysis of the molecular pathways that cause major neurodegenerative diseases, discusses the physiological and physicochemical barriers to drug delivery to the brain, and reviews the most recent drug targeting strategies including receptor-mediated transcytosis, cell-based “Trojan horse” approaches, gene-editing vectors, and spatiotemporally controlled physical methods. The review also critically evaluates the limitations such as immunogenicity, scalability, and clinical translation challenges, proposing potential solutions to enhance therapeutic efficacy. The recent clinical trials are assessed in detail, and current and future trends are discussed, including artificial intelligence (AI)-based carrier engineering, combination therapy, and precision neuro-nanomedicine. The successful translation of these innovations into effective treatments for patients with neurodegenerative diseases will require essential interdisciplinary collaboration between neuroscientists, pharmaceutics experts, clinicians, and regulators. Full article
(This article belongs to the Special Issue Targeted Therapies and Drug Delivery for Neurodegenerative Diseases)
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