Aug 2026· Journal of Controlled Release· Vol 398, pp.
115219
· 0 citations· 52 references
Medicine
TL;DR
This discussion aims to inspire a reorientation of nanomedicine strategies toward precision therapy for epilepsy by highlighting how emerging nanomedicines are expanding the therapeutic target repertoire to include key non-neuronal nodes, with a focus on neuroinflammation and BBB repair.
Abstract
Epilepsy remains a major neurological disorder characterized by unpredictable seizures and cumulative comorbidities that even endure with standard pharmacotherapy. Conventional antiepileptic drugs (AEDs) are constrained by two interrelated barriers: limited brain penetration due to the blood-brain barrier (BBB), which necessitates high systemic dosing and peripheral toxicity, and a narrow mechanistic focus on neuronal ion channels and synaptic receptors. This neuron-centric view overlooks non-neuronal drivers, such as neuroinflammation and BBB dysfunction, that sustain epileptogenesis and contribute to drug resistance in roughly one-third of patients. Nanomedicine addresses these limitations through a fundamentally different approach. Leveraging the unique advantages of nanocarriers, including facile synthesis, surface modification, and receptor-mediated BBB transcytosis, nanoparticles have evolved from passive delivery vehicles into intelligent, multifunctional therapeutic platforms that actively engage with disease biology. In this Perspective, we first delineate the inherent limitations of conventional AEDs in target selection. We then highlight how emerging nanomedicines are expanding the therapeutic target repertoire to include key non-neuronal nodes, with a focus on neuroinflammation and BBB repair. Finally, we offer a forward-looking perspective on two emerging frontiers: modulation of metabolic dysregulation and the microbiota-gut-brain axis, as well as the development of theranostic nanoplatforms that integrate real-time seizure monitoring with closed-loop intervention. Through this discussion, we aim to inspire a reorientation of nanomedicine strategies toward precision therapy for epilepsy.
OBJECTIVES
Epilepsy is a chronic neurological disorder affecting nearly 50 million people worldwide and is characterized by recurrent seizures caused by abnormal neuronal activity. Conventional therapies, including antiepileptic drugs, growth factors, and gene therapy, are often limited by poor blood-brain barrier (BBB) penetration, drug resistance, adverse effects, and low bioavailability. This review summarizes recent advances in nanocarrier-based drug delivery systems for improving epilepsy treatment.
METHODS
A comprehensive review of peer-reviewed articles, patents, and clinical studies was conducted to evaluate lipid-based, vesicular, polymeric, dendrimer, and inorganic nanocarriers. Their formulation strategies, BBB transport mechanisms, therapeutic applications, clinical progress, and future prospects were critically analysed.
KEY FINDINGS
Nanocarriers enhance the solubility, stability, bioavailability, controlled release, and brain targeting of antiepileptic drugs. Liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, dendrimers, nanoemulsions, and metallic nanoparticles have demonstrated improved BBB penetration, prolonged drug action, reduced toxicity, and enhanced seizure control in preclinical studies. Despite promising outcomes, challenges related to large-scale manufacturing, long-term safety, regulatory approval, and clinical translation remain.
CONCLUSIONS
Nanomedicine represents a promising approach for overcoming the limitations of conventional epilepsy therapy by enabling efficient brain-targeted drug delivery. Further optimization, safety evaluation, and clinical validation are essential to support the successful translation of nanocarrier-based therapies into clinical practice.
Abhishek Chauhan, Ankush Kumar, Ankit Awasthi et al.· The Journal of pharmacy and...· 0 citations
Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability, and 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.
Wonseok Chang, Amy Seomin Kwak, Seung-Ho Han et al.· Pharmaceutics· 0 citations
Abstract In this review, treatment-resistant depression (TRD),a clinically defined subtype of major depressive disorder, is characterized by substantial disease burden and heterogeneous pathophysiology, with many patients showing inadequate or transient responses to currently available pharmacological therapies. Emerging evidence indicates that some treatment failures may reflect limitations in central nervous system (CNS) drug delivery in addition to disease heterogeneity and pharmacological factors. TRD treatment failure from a drug-delivery perspective is reviewed here, and barriers such as the problem of crossing the blood-brain barrier, mismatch in drug distribution, and insufficient local PK/PD or target binding are listed. Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) is expected to be a method for targeted drug delivery to a specific area in the brain at a particular time, and it is not a standalone treatment for depression. FUS-BBBO has shown some preliminary clinical feasibility and safety in several CNS disorders, including neuro-oncology and neurodegenerative diseases, and is expected to be used as a new type of CNS drug delivery system. However, its application in TRD is still in the theoretical stage and requires disease-specific validation. To address target heterogeneity, spatial transcriptomics and single-nucleus multi-omics have been proposed in the review as necessary ways to optimise target selection. The above ways can increase the precision of the target Area by providing cell-type and molecular-level information that is unavailable in traditional imaging-based localisation methods, thereby improving the precision of therapeutic targeting. The medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala are potential target areas. Each connected to specific disease mechanisms and necessitating unique therapeutic agents. Finally, the review proposes a three-step translational framework—patient stratification, target constraint, and cargo matching—and delineates five interlinked clinical development barriers: long-term safety of repeated BBB opening, technical standardization and reproducibility, quantifiable intracerebral PK, biological hit verification, and mechanism-enriched trial design. We propose that the translational potential of FUS-BBBO in TRD may be realized through a closed-loop precision-therapy framework. This framework integrates patient stratification, region-specific delivery, pharmacodynamic verification, and mechanism-matched cargo selection.
Chungang Zhang, Deyu Fang, Lin Zhang· Drug Design, Development and...· 0 citations
Depression is a leading global health burden, yet current pharmacotherapy remains constrained by depression-specific challenges that extend beyond simple blood-brain barrier (BBB) penetration, including delayed onset of action, poor regional brain specificity, and the inability to deliver emerging biologics. Engineered nanomedicine offers a paradigm-shifting platform to address these limitations through precise designs such as receptor-mediated transport and cell-mimetic carriers, enabling targeted modulation of depression-related neural circuits. This review critically evaluates advanced nanoengineering strategies for antidepressant delivery, distinguishing proof-of-concept systems from platforms with realistic translational potential. We further provide a decision-oriented framework to guide future clinical development. By moving beyond generic strategies for BBB penetration to address the distinctive pharmacotherapeutic shortcomings of depression, engineered nanomedicine holds great promise for advancing next-generation antidepressant therapies that achieve rapid onset, precise intervention, and comprehensive improvement in patient quality of life.
Mijia Zhang, En-Yao He, Y. Xiong et al.· Advanced Healthcare Material...· 0 citations
Glioblastoma (GBM) remains one of the most aggressive primary brain tumors, with poor prognosis, high recurrence, and limited therapeutic options. Although substantial progress has been made in drug development, effective clinical translation is still constrained by inefficient delivery across the blood brain barrier (BBB) and blood brain tumor barrier (BBTB), insufficient tumor accumulation, intratumoral heterogeneity, acquired therapeutic resistance, and dose limiting systemic toxicity. Nanomedicine offers a promising strategy to address these barriers through tunable physicochemical properties, flexible surface functionalization, improved pharmacokinetics, and controllable drug release. In this review, we systematically summarize recent advances in nanomedicine enabled GBM therapy from four interrelated perspectives: the optimization of nanomaterial properties, the development of goal-oriented targeting strategies, the rationalization of delivery routes, and the engineering of smart stimuli-responsive nano-systems. Rather than only cataloguing representative nanoplatforms, we emphasize how material parameters, biological targeting mechanisms, delivery routes, and release behaviors are mechanistically linked to BBB or BBTB penetration, tumor accumulation, therapeutic efficacy, and translational feasibility. Importantly, we also incorporate a key failure case analysis of representative clinical and preclinical studies, highlighting why promising nanotherapeutic concepts may fail because of inadequate intratumoral distribution, insufficient survival benefit, poor patient selection, manufacturing complexity, safety concerns, or impractical trial design. By integrating delivery mechanisms, cross platform comparison, translational barriers, and future optimization principles, this review provides a critical and forward looking framework for the rational design of precise, effective, and clinically translatable nanomedicine strategies for GBM treatment.
Yu Guo, Keqiang Lu, Wenmiao Luo et al.· Wiley Interdisciplinary Revi...· 1 citation
Migraine represents a complex neurovascular disorder that is challenging to treat due to the blood-brain barrier (BBB) and complex pathophysiology involving the trigeminovascular system, neuroinflammation, and cortical spreading depression. Current systemic therapies, including calcitonin gene-related peptide (CGRP) inhibitors, offer benefits but have limited efficacy and may cause adverse effects; thus, highlighting the need for targeted delivery across the BBB. This review introduces extracellular vesicles (EVs) as an appropriate pharmaceutical engineering platform to address such challenges. While traditional treatments have inherent disadvantages, engineered EVs offer efficient blood-brain barrier (BBB) penetration, targeted delivery, and multi-therapeutic payload capacity for migraine-associated neural circuits. We introduce a framework for pathophysiology-informed technology by first discussing the role of native EVs in promoting the migraine cascade to identify specific sites of therapeutic intervention. In this review, the focus is on pharmaceutical nanotechnology, starting with the strategic selection of producer cells, including "Hijack & Modify" vs De Novo Design, and continuing through sequential nano-engineering of EVs by surface functionalization and utilization of hybrid vesicles for targeting the BBB and trigeminovascular systems to state-of-the-art smart-release systems. We continue with the critical analytical and manufacturing sciences needed to translate such engineered EVs from bench to bedside, addressing important translational challenges through scalable Good manufacturing practices (GMP) production, supported potency assays, and comprehensive quality assurance processes. These include potency tests, GMP production, and robust quality control that may be expanded. Finally, we combine all of these into a single translational pathway that examines the regulatory issues, the patent landscape, and the future of personalized EV therapeutics. The current review provides an exhaustive framework for developing EV-based treatments by combining cutting-edge pharmaceutical nanotechnology with deep biological insights to make migraine treatment more reliable.
Abhirami Subramony, V. K. Patel, Siva Syam Kumar et al.· ACS Applied Bio Materials· 0 citations