Systematic review of optimizing brain-targeted vitamin D delivery: Novel approaches to enhance mental illness therapeutics
Brain Research https://doi.org/10.1016/j.brainres.2025.149656 behind $38 paywall
Jinghu He a 1, Zhiyuan Gao b , Xilian Li c 1, Long Zhao d, Xue Tian e, Biao Gao f
a Department of General Surgery, Shanghai No. 411 Hospital, RongTong Medical Healthcare Group Co., Ltd., Changhai Hospital, 200081, China
b Yueyang Integrated Traditional Chinese and Western Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
c Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China lixilian8157 at fckyy.org.cn
d The 988th Hospital of PLA Joint Logistics Support, Zhengzhou 450042 Henan Province, China
e Department of Nutrition, Cangzhou Central Hospital, Cangzhou 061012 Hebei, China daxuefenfen at 163.com
f Teaching and Research Support Center, Naval Medical University, Shanghai 200433, China gaobiao at smmu.edu.cn
Highlights
- First systematic review on brain-targeted vitamin D delivery strategies aimed at improving the efficacy of mental illness treatments.
- Nanotechnology and biotin conjugation can enhance vitamin D BBB permeability and transport efficiency.
- Intranasal and transdermal administration routes effectively bypass first-pass metabolism and blood–brain barrier obstacles.
- Modulating the VDR-P-gp signaling pathway offers new targets for improving blood–brain barrier permeability.
Background
Vitamin D is increasingly recognized for its neuroprotective, anti-inflammatory, and immunomodulatory roles in mental health. However, its delivery to the central nervous system remains constrained by various factors.
Objective
This systematic review evaluates strategies for optimizing brain-targeted vitamin D delivery, highlighting molecular, physiological, and technological approaches to enhance its efficacy in mental disorders.
Methods
Following PRISMA guidelines, a comprehensive search across PubMed, Web of Science, Scopus, Embase, and PsycINFO was conducted. Relevant studies were assessed thematically, focusing on BBB transport mechanisms, nanocarriers, structural modifications, and transporter-mediated delivery.
Results
Strategies including nanotechnology, biotin-based transporter targeting (e.g., SMVT/SLC5A6), DBP–Megalin/Cubilin-mediated transcytosis, and intranasal administration show promise in enhancing vitamin D brain uptake. Differences between serum and brain vitamin D concentrations, genomic and non-genomic VDR pathways, and psychiatric disorder-specific associations (e.g., depression, schizophrenia, ASD) were also examined.
Conclusions
Although limited by the scarcity of large-scale clinical data, emerging strategies demonstrate significant potential in enhancing brain-targeted vitamin D delivery. These findings lay a foundation for future translational research aimed at precision mental health interventions.
Introduction
Mental health has become a significant public health challenge worldwide. An estimated 13 % of the global population suffers from mental disorders, which severely compromises patients' quality of life and imposes a heavy burden on families and society (Revankar). Although existing treatments have made certain advances, they often demonstrate limited efficacy, significant side effects, and poor patient compliance, underscoring the urgent need for novel therapeutic strategies (Baryakova et al., 2023). Vitamin D, well known for its role in bone and calcium-phosphorus metabolism, exerts extensive biological functions in various tissues and organs (Mirarchi et al., 2023, Gil et al., 2018). In particular, its antioxidant capacity (Michel et al., 2010, Da Silva Souza et al., 2020), anti-inflammatory properties (Peelen et al., 2011), immune-regulatory effects (Müller, 2017), and promotion of neuronal development (Anjum et al., 2018) provide a robust theoretical basis for its application as an adjunct therapy in mental disorders.
Active vitamin D includes vitamin D2(ergocalciferol) and vitamin D3(cholecalciferol); the former is derived from plants and is in lower amounts, while the latter can be obtained from dietary sources and exhibits higher potency. However, the primary source of vitamin D3 in humans arises from the cutaneous synthesis of 7-dehydrocholesterol(7-DHC) under ultraviolet B(UVB) irradiation. Maintaining serum 25(OH)D3 levels within the 30–60 ng/mL range is critical to preventing adverse health outcomes (Glowka et al., 2019). Unfortunately, modern lifestyles characterized by reduced outdoor activities and reliance on processed foods have led to widespread vitamin D deficiency, posing another significant public health concern (Nascimento et al., 2023, Alnafisah et al., 2024, Gillie, 2011). Research found that globally, the proportions of individuals with serum 25-hydroxyvitamin D levels below 12, 20, and 30 ng/mL are approximately 15.7 %, 47.9 %, and 76.6 %, respectively. (Cui et al., 2023). Table 1 summarizes the global prevalence of representative mental disorders, their association with vitamin D deficiency, and potential benefits of supplementation.
Notably, vitamin D and its receptor (VDR) are expressed in both neurons and endothelial cells of the brain, where they play pivotal roles in regulating the cerebral microenvironment (Iwaki et al., 2023, Kim et al., 2020). They are closely linked to the pathogenesis of various psychiatric conditions (Ganji et al., 2010, Wilkins et al., 2006, May et al., 2010, Kjærgaard et al., 2012, Postolache et al., 2020, Milaneschi et al., 2014), particularly depression, schizophrenia, and autism spectrum disorders (Hung et al., 2023). Vitamin D deficiency not only increases the susceptibility and severity of these disorders (Durk et al., 2014, Buell et al., 2010, Kaloglu et al., 2016) but also highlights vitamin D as a promising pharmacological intervention (Vellekkatt et al., 2020), with the potential to mitigate symptoms (Khoraminya et al., 2013) and reduce incidence rates (Wu et al., 2022).
Despite its therapeutic promise, vitamin D encounters significant challenges in clinical application. The blood–brain barrier (BBB), composed of tightly connected endothelial cells, basement membranes, and astrocytes, effectively shields the brain from harmful exogenous substances while substantially limiting drug permeability (Kadry et al., 2020, Alahmari, 2021). Current evidence indicates several mechanisms by which vitamin D traverses the BBB: (1) passive diffusion driven by concentration gradients (Zelzer et al., 2021); (2) carrier-mediated transport, where Megalin and Cubilin multifunctional endocytic receptors in renal tubular endothelial cells endocytose and transport the DBP–vitamin D complex, a process also observed in extra-renal tissues (Khan et al., 2022, Beydoun et al., 2017, Christensen and Birn, 2002); (3) membrane transporters, especially those belonging to the solute carrier family (SLC) (Revez et al., 2020); and (4) receptor-mediated transcytosis (RMT) possibly facilitated indirectly by VDR in endothelial cells (Takahashi et al., 2022, Alam et al., 2019). Nevertheless, these pathways generally exhibit suboptimal efficiency, limiting vitamin D's efficacy in brain disorders (Pardridge et al., 1985).
To overcome the bottleneck posed by low BBB permeability of vitamin D and fully leverage its therapeutic potential in mental disorders, researchers have explored diverse approaches to enhance its brain-targeted delivery or to identify novel administration routes for efficient cerebral uptake. However, a comprehensive review of these strategies is still lacking, and most studies focus on single modifications or specific carriers without a holistic, multifactorial optimization perspective. In this review, we systematically examine strategies that increase vitamin D transport across the BBB and discuss their implications for advancing the prevention and treatment of mental illnesses.
Section snippets
Data sources
To ensure comprehensiveness and representativeness, this review systematically searched five major databases: PubMed, Web of Science, Scopus, Embase, and PsycINFO. Additionally, supplementary searches were conducted in ProQuest, the Derwent World Patents Index (DWPI), Google Scholar, and the China National Knowledge Infrastructure (CNKI). The search covered the period from 2010 to 2024, and only English-language publications were included.
Search strategy
This study adhered to the PRISMA guidelines and followed …
Literature search results
A preliminary search retrieved a total of 917 articles, including 99 from PubMed, 249 from Web of Science, 377 from Scopus, 166 from Embase, and 26 from PsycINFO. After importing all records into NoteExpress (Revision 4.1.0.9990) and removing 291 duplicates, 628 unique articles remained. Following a title and abstract screening, 112 articles met the initial inclusion criteria. Subsequently, a full-text review and quality assessment were performed, and 5 additional studies identified by snowball …
Discussion
This review examined strategies to enhance the potential therapeutic effects of vitamin D in mental disorders, focusing on its mechanisms and challenges related to crossing the BBB. Despite comprehensive literature searches, only eight studies were included in the core analysis, indicating a relatively low level of attention in this field.
Conclusion
Vitamin D is closely associated with the onset, progression, and severity of mental disorders. However, its therapeutic potential has not been fully realized due to the influence of multiple complex factors. Various strategies, including molecular modifications, transporter-mediated approaches, and nanotechnology, have enhanced the bioavailability and BBB permeability of vitamin D. Additionally, innovative delivery routes, such as transdermal and intranasal administration, have shown …
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Some related items in VitaminDWiki
- The founder of VitaminDWiki has been occasionally inhaling a nanoemulsion form of Vitamin D into his lungs and brain
Inhaling Vitamin D nanoemulsion through nose gets lots more to the brain (mice) – July 2020
Perhaps drugs such as inhaled vitamin D can get directly to the brain – March 2018
Topical Vitamin D provides more benefits than oral sometimes - many studies
Nanoemulsion Vitamin D is faster and better - many studies
Brain and Vitamin D - many studies
Alzheimer’s 4X less likely with high level of vitamin D – 2 studies April 2012