Search Results (117)

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions. Full article

Rabies remains one of the clearest therapeutic paradoxes in infectious diseases: it is largely preventable before neuroinvasion, yet once clinical symptoms appear, mortality approaches 100%. This sharp transition reflects more than delayed diagnosis alone. Wild-type rabies virus reaches and spreads within the central nervous system under conditions of relative immune silence, while the blood–brain barrier (BBB) severely restricts the entry of circulating immune effectors, including virus-neutralizing antibodies. As a result, conventional immunotherapy, although highly effective in post-exposure prophylaxis, performs poorly after symptom onset because it no longer reaches the relevant compartment. This review examines whether engineered antibodies can overcome that limitation and provide a realistic path toward brain-targeted rabies immunotherapy. We first outline why symptomatic rabies remains refractory to standard immune intervention, emphasizing the combined roles of viral immune evasion and BBB-mediated anatomical exclusion. We then review recent proof-of-concept studies showing that antibody-based rescue after central nervous system invasion is biologically plausible, particularly when antibodies are delivered directly into the central nervous system (CNS), retain Fc-dependent immune activity, or are modified to improve BBB penetration. Building on these findings, we discuss key design principles for next-generation therapeutics, including epitope breadth, resistance to viral escape, Fc tuning, and delivery modules based on peptide shuttles or receptor-mediated transcytosis platforms such as TfR1- and CD98hc-targeted systems. Finally, we highlight the major translational barriers that still separate experimental rescue from clinical therapy, including the narrow therapeutic window, model limitations, safety concerns, ethical issues, implementation constraints, and the need for standardized endpoints. Full article

Traumatic brain injury (TBI) is a prevalent neurological disorder that induces severe neurological dysfunction and markedly reduces quality of life owing to its complex pathophysiology and limited therapeutic options. Conventional pharmacological and surgical interventions show restricted efficacy because of poor blood–brain barrier penetration and inability to address secondary injury cascades. In recent years, hydrogels have shown significant potential for TBI repair due to their superior biocompatibility, high water content, and ability to mimic the native extracellular matrix (ECM). This review systematically examines recent advances in hydrogel applications for TBI therapy, focusing on their roles as drug delivery platforms, stem cell scaffolds, neuroregeneration promoters, inflammation modulators, and angiogenesis facilitators. Particular emphasis is placed on the therapeutic benefits and underlying mechanisms of ECM-derived hydrogels, self-assembling peptide (SAP) hydrogels, stimuli-responsive smart hydrogels, and functionalized multicomponent systems. Current challenges and limitations in hydrogel applications are also discussed, along with future research directions, to provide scientific rationale and practical guidance for precision TBI therapy. Full article

Adeno-associated viruses (AAVs) are a promising gene therapy technology, but major technical challenges remain. One problem is that commonly used AAVs have a low efficiency in penetrating the blood–brain barrier (BBB) and the blood–retina barrier (BRB). Consequently, gene delivery to the nervous system has limitations. Another problem is that AAVs induce immune reactions that cause serious side effects. To avoid immune reactions, the AAV dose must be reduced to lower levels that may result in insufficient gene delivery. Researchers have been modifying viral capsid protein sequences and searching for effective peptide sequences to solve these problems. As a result, Cell-Penetrating Penta-Peptides (CPP5s) have been shown to be effective in improving the BBB/BRB penetration of AAVs and suppressing immune reactions against AAVs. CPP5s were originally developed from peptide sequences of the Bax (a pro-apoptotic protein) binding domain of Ku70 (a DNA repair protein) and from negative control cell-penetrating peptides without Bax-binding activity. This article will discuss the background science of CPP5s and future directions of CPP5s for AAV-mediated gene delivery to the nervous system as well as other organs. Full article

Background: Mitochondrial dysfunction in microglia is an important pathogenic factor inducing the onset of Parkinson’s Disease (PD). To address this challenge, a novel hierarchical nano-delivery system was developed to deliver a PD therapeutic agent, wedelolactone (WED) to modulate mitochondrial dysfunction. Methods: The nano-delivery system (WED@RBCm-B6&RAP12-NPs) was coated with red blood membrane (RBCm) to avoid immune clearance and conjugated with the BBB-penetrating peptide CGHKAKGPRK (B6) and the microglia targeting peptide EAKIEKHNHYQK (RAP12). Results: The experimental results demonstrated that this novel nano-delivery system could increase its half-life in blood circulation effectively via evading immune recognition and clearance and enhanced its brain distribution by synergistic effect of B6 and RAP12. By specifically targeting microglia in PD mouse brain, the system increased pyruvate dehydrogenase (PDH) activity, leading to mitochondrial structural repair, reduced secretion of pro-inflammatory cytokines, and improved the inflammatory microenvironment. Conclusions: The result first designed and synthesis a dual targeting drug delivery system WED@RBCm-B6&RAP12-NPs which significantly alleviated mitochondrial dysfunction and warranted further study to develop therapeutic agent for PD treatment. Full article

BNCT (Boron Neutron Capture Therapy) is a binary radiotherapeutic modality in which high LET (Linear Energy Transfer) particles are generated from ¹⁰B(n,α)⁷Li reaction, ideally within boron-loaded tumour cells, so the therapeutic outcome depends critically on the pharmacokinetics and biodistribution of boron carriers. In this review, boron-containing agents for BNCT, with a focus on ADMET (absorption, distribution, metabolism, excretion and toxicity) and model-informed design, were examined. Low-MW (low-molecular-weight) compounds, peptide conjugates, polymeric and nanostructured platforms and cell-based vectors were surveyed and how physicochemical properties, transporter engagement and nano–bio interactions govern tumour uptake, subcellular localisation and normal tissue exposure were discussed. A shift from maximising boron content towards optimising exposure profiles using PET (Positron Emission Tomography), PBK (physiologically based pharmacokinetic) modelling and in silico ADMET tools to define irradiation windows was also discussed. Classical agents such as BPA (Boronophenylalanine) and BSH (Sodium Borocaptate) are contrasted with newer polymeric and metallacarborane-based carriers, with attention to brain penetration, endosomal escape, linker stability, biodegradation and elimination routes, as well as platform-specific toxicities. Incontestably, further progress in BNCT will highly depend on integrating imaging-derived kinetics with PBPK-informed dose planning and engineering subcellularly precise yet degradable carriers, and that ADMET-guided design and spatiotemporal coordination are central to achieving reproducible clinical benefit from BNCT’s spatial selectivity. Full article

Glioblastoma, with a 5-year survival rate of just under 7.0%, is the most common form of brain cancer in adults. In this study, we evaluated the antiproliferative activity of the biopolymer p21-ELP1-Bac, a p21-derived peptide delivered via an elastin-like polypeptide (ELP1) carrier and a cell-penetrating peptide (CPP), across three glioblastoma cell lines: U87, GBM43, and GBM6. We assessed proliferation, cell cycle progression, and apoptosis to determine whether ELP-mediated intracellular delivery of p21-ELP1-Bac suppresses glioblastoma growth through cytostatic mechanisms rather than inducing apoptosis. Treatment with the modified protein effectively inhibited proliferation across all three lines, with U87 cells showing the greatest sensitivity and GBM6 cells demonstrating the greatest drug tolerance. Although apoptotic responses were generally low, they appeared more pronounced in GBM6 cells. Confocal microscopy revealed sustained cellular uptake and signal observed in both the cytoplasm and in proximity to the nucleus in all cell lines. Collectively, these findings indicate that p21-ELP1-Bac is efficiently internalized and capable of modulating proliferation across all three glioblastoma cell lines, supporting its further evaluation as a cytostatic delivery platform. Full article

Synucleinopathies, including Parkinson’s disease (PD), are neurodegenerative disorders characterized by aberrant aggregation of α-synuclein (α-syn), a presynaptic protein with an intrinsic disorder nature. The transition of soluble monomers into oligomeric and fibrillar species represents a key molecular event driving neuronal dysfunction and neurodegeneration. Emerging evidence suggests that nutraceuticals, bioactive compounds derived from dietary sources, can modulate α-syn aggregation at multiple conformational stages. Polyphenols, alkaloids, ginsenosides, and food-derived peptides interfere with α-syn structure and assembly, suppressing the formation of toxic oligomer species and promoting the clearance of misfolded assemblies. Despite this potential, clinical translational of nutraceuticals is currently limited by poor systemic bioavailability and restricted central nervous system penetration due to blood–brain barrier constraints, which have largely confined research to preclinical studies. In this context, this review summarizes current knowledge of nutraceutical interventions targeting the conformational landscape of α-syn and highlighting both direct and indirect molecular mechanisms with involved in aggregation-prone species. Furthermore, we critically examine key challenges related to bioavailability and clinical translation, focusing on advanced delivery systems and precision-based approaches to enhance neuroprotective efficacy and support the potential of nutraceuticals as novel or adjunctive therapeutic strategies for PD. Full article

Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K/Akt, MAPK/ERK, cAMP/PKA–CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood–brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD. Full article

Background/Objectives: Cell-mediated and peptide-assisted delivery systems have emerged as powerful platforms at the intersection of chemistry, nanotechnology, and molecular medicine. By leveraging the intrinsic targeting, transport, and signaling capacities of living cells and bioinspired peptides, these systems facilitate the delivery of therapeutic agents across otherwise restrictive biological barriers such as the blood–brain barrier (BBB) and the tumor microenvironment. This review aims to summarize recent advances in engineered cell carriers, peptide vectors, and hybrid nanostructures designed for enhanced intracellular and tissue-specific delivery. Methods: We surveyed recent literature covering molecular design principles, mechanistic studies, and in vitro/in vivo evaluations of cell-mediated and peptide-enabled delivery platforms. Emphasis was placed on neuro-oncology, immunotherapy, and regenerative medicine, with particular focus on uptake pathways, endosomal escape mechanisms, and structure–function relationships. Results: Analysis of current strategies reveals significant progress in optimizing cell-based transport systems, peptide conjugates, and multifunctional nanostructures for the targeted delivery of drugs, nucleic acids, and immunomodulatory agents. Key innovations include improved BBB penetration, enhanced tumor homing, and more efficient cytosolic delivery enabled by advanced peptide designs and engineered cellular carriers. Several platforms have progressed toward clinical translation, underscoring their therapeutic potential. Conclusions: Cell-mediated and peptide-assisted delivery technologies represent a rapidly evolving frontier with broad relevance to next-generation therapeutics. Despite notable advances, challenges remain in scalability, manufacturing, safety, and regulatory approval. Continued integration of chemical design, molecular engineering, and translational research will be essential to fully realize the clinical impact of these delivery systems. Full article

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumour with limited treatment options and a poor prognosis. Therapeutic failure is driven by multiple barriers, including the blood–brain barrier (BBB), the tumour microenvironment (TME), and intratumoural heterogeneity. Conventional delivery systems often fail to achieve sufficient drug accumulation or controlled release within the tumour. In this review, we outline a theoretical framework for the design of ligand-functionalised magnetic lipid nanoparticles (MF-R-LNs), a multifunctional nanoplatform that integrates active targeting, stimuli-responsive drug release, and external magnetic-field control. The proposed MF-R-LNs incorporate superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic guidance and hyperthermia; polyethylene glycol (PEG) for extended circulation; and surface ligands such as peptides, antibodies, or aptamers to target GBM-specific receptors including epidermal growth factor receptor (EGFR), Interleukin-13 receptor alpha-2 (IL-13Rα2), and integrins. Triggered release mechanisms such as pH-sensitive lipids, redox cleavable linkers, and enzyme-responsive coatings enable selective drug release within the TME. Magnetic hyperthermia serves as both a therapeutic modality and a remote trigger to enhance release and tumour penetration. This modular design offers a theoretically robust strategy to overcome the key physiological and therapeutic barriers in GBM. We discuss the rationale behind each design feature, explore potential synergies, and highlight translational challenges such as tumour heterogeneity, manufacturing complexity, and safety concerns. Despite encouraging preclinical evidence, clinical translation faces substantial hurdles, notably patient-specific heterogeneity and scalable GMP manufacturing/characterisation of multi-component nanoplatforms. While preclinical validation remains necessary, this framework may inform future efforts to develop spatiotemporally controlled, multifunctional therapeutics for glioblastoma. This manuscript is a conceptual framework review that synthesises current strategies into actionable guidance for designing and reporting MF-R-LNs for GBM. Full article

The relationship between the structure of walnut-derived peptides and their activity of transport efficiency across the blood–brain barrier (BBB) remains unclear. In this study, a series of walnut-derived peptides were synthesized by substituting leucine (L) with tyrosine (Y), lysine (K), or arginine (R). Three outstanding peptides—EVSGPGYSPN, TWLPYPR, and YVPFPYP—were selected based on their antioxidant capacity and BBB transport efficiency, with EVSGPGYSPN exhibiting the highest activity. Reversed-phase high-performance liquid chromatography (RP-HPLC) and Transwell assay results demonstrated that EVSGPGYSPN can remain stable during gastrointestinal digestion and penetrate the BBB. Pharmacokinetic results revealed that the cumulative concentration of EVSGPGYSPN in the brain reached 1.25 ± 0.91 µg/g at 10 h, while its plasma half-life exceeded 12 h. Furthermore, it significantly reduced reactive oxygen species (ROS) levels to 110.46 ± 15.16%. Nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR) results indicated that EVSGPGYSPN is rich in aromatic hydrogen signals and exhibits low methyl signals, which may enhance its antioxidant activity. Circular dichroism (CD) spectroscopy showed that EVSGPGYSPN has the highest random coil content, which facilitates its binding to transporters on the BBB and promotes BBB permeability. This study provides valuable insights into the design of brain-targeted peptide delivery systems. Full article

Background/Objectives: Nanocrystals (NCs) are a relatively underexplored yet adaptable platform with broad potential for various applications. Currently, the surface modification of NCs leads to the development of versatile platforms capable of enhancing targeted delivery potential and supporting the advancement of precision medicine. With this in mind, this study focused on the design and surface functionalization of a resveratrol (RSV) NC selected for its antioxidant and neuroprotective effects. Methods: The design of the RSV NC was assessed by the Quality by Design approach. With the aim of intranasal administration, we assessed the RSV NC functionalization with a cationic poly (amino acid) belonging to the class of cell-penetrating peptides. Both naked and surface-modified RSV nanosuspensions were characterized in terms of mucoadhesion, behavior in artificial cerebrospinal fluid, crystallinity, solubility, and storage stability. The scavenging activity (%) of neat RSV and its nanosized forms was measured using the DPPH assay. Results: RSV NCs were successfully designed, producing truncated cubic crystals (~240 nm) with an ~80% drug content. Functionalization was efficiently achieved with poly-l-arginine hydrochloride as revealed by DSC and FTIR and resulted in a positively charged nanosuspension. Nanonization technology improved drug solubility in water and did not affect RSV scavenging activity. Technological characterization demonstrated that both nanosuspensions present suitable properties for intranasal administration in terms of particle size, mucoadhesive tendency, and stability in artificial cerebrospinal fluid. An MTT assay revealed the safety of all treatments in human microglia (HMC3) cells. Conclusions: RSV NCs’ functionalization enhanced their brain delivery potential, establishing a promising platform to improve therapeutic outcomes in neurodegenerative diseases. Full article

Alzheimer’s disease (AD) drug development faces persistent challenges from blood–brain barrier limitations and inadequate integration of medicinal chemistry considerations with computational predictions. We developed a comprehensive Central Nervous System (CNS)-focused network medicine framework integrating machine-learning-validated BBB penetration prediction (95.7% accuracy, 0.992 AUC-ROC), modality-specific tractability assessment, and transparent evidence classification to identify viable drug repurposing candidates. CNS-specific pre-filtering refined 24,474 DGIdb compounds to 8247 CNS-relevant drugs, analyzed through multi-dimensional network scoring and systematic pharmaceutical property assessment. Modality stratification generated separate rankings for small molecules (3667 candidates), peptides (73 candidates), and biologics (3 candidates), acknowledging distinct BBB penetration mechanisms. Analysis revealed 64.8% of small molecules achieving Class I (Highly Tractable) status, with 83.6% demonstrating favorable BBB penetration. Plerixafor emerged as the top-ranked small molecule (score: 1.170), while trofinetide achieved the highest peptide ranking (score: 1.387), though classified as speculative, pending AD-specific validation. Successful identification of the FDA-approved AD therapeutics memantine and donepezil among the top candidates validated the computational performance, while the predominance of mechanistic evidence classifications (86.7%) highlighted that network predictions represent hypothesis-generating tools requiring systematic experimental validation rather than definitive therapeutic recommendations. The framework bridges computational predictions with pharmaceutical development requirements, providing actionable prioritization for systematic preclinical investigation addressing AD intervention. Full article

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article