Dual-modulation of nutrient-transporter axis and functionalized carriers: A paradigm shift for precision oral vitamin D delivery
Colloids and Surfaces B: Biointerfaces Volume 253, September 2025,
https://doi.org/10.1016/j.colsurfb.2025.114769 FULL PDF is behind a paywall
Zixiao Wang. Yixiang Liu
Highlights
Transport proteins localized at the apical membrane of intestinal epithelial cells mediate vitamin D uptake.
Some dietary components can positively regulate the expression or activity of lipid transporters.
The novel "nutrient-transporter-vitamin D axis" strategy was proposed for developing delivery platform.
Nutraceutical-delivery vector integration engineering potentiates oral vitamin D bioavailability
The transintestinal epithelial absorption of vitamin D is intricately regulated by specific transport protein networks. Emerging evidence from molecular nutrition research reveals that certain dietary nutrients can enhance intestinal vitamin D absorption through targeted modulation of lipid transport pathways. Despite significant advancements in vitamin D delivery systems demonstrating excellent intestinal mucoadhesion and in vitro bioaccessibility, their clinical translation remains limited by suboptimal in vivo bioavailability. To address this critical challenge, we propose an innovative synergistic nutrient absorption strategy that establishes precise coordination among three key elements: dietary nutrient composition, transport protein regulation, and intestinal absorption optimization. This comprehensive review systematically examines: (1) The molecular mechanisms governing transintestinal vitamin D transport and physiological modulation of protein-mediated absorption pathways; (2) The regulatory effects of dietary components on vitamin D absorption efficiency through protein pathway modulation, proposing a novel "nutrient-transporter-vitamin D axis" strategy integrating cutting-edge carrier technologies; (3) Future perspectives for developing functionalized vitamin D delivery systems. The proposed paradigm shift, combining nutrient-mediated transport enhancement with advanced carrier engineering, represents a transformative approach to overcome current limitations in oral vitamin D delivery. This dual-modulation strategy synergistically improves intestinal absorption and systemic bioavailability through simultaneous optimization of biological transport mechanisms and pharmaceutical delivery parameters, offering new possibilities for precision nutrition interventions.
Introduction
Vitamin D, an essential lipophilic micronutrient, faces significant challenges in oral delivery due to inherent physicochemical constraints including poor aqueous solubility, photochemical instability, and oxidation susceptibility during gastrointestinal processing. These limitations are compounded by its regulated transintestinal transport mediated by sterol-binding proteins, creating dual barriers of inefficient epithelial permeation and enzymatic degradation that collectively restrict systemic bioavailability. Clinically, the National Osteoporosis Society defines vitamin D deficiency (VDD) as serum 25(OH)D < 30 nmol/L (deficiency) and 30–50 nmol/L (insufficiency), with global epidemiological studies revealing alarming prevalence rates - affecting 40 % of European adults and reaching 80 % in Middle Eastern populations [1], [2], [3]. This metabolic deficiency state precipitates multiorgan pathophysiology, extending beyond classical skeletal disorders (rickets/osteomalacia) to encompass chronic inflammatory conditions, autoimmune dysregulation, and cardiovascular comorbidities [4], [5], [6]. Current interventions for vitamin D deficiency primarily rely on three approaches: sunlight exposure, fortified foods, and pharmaceutical supplementation. While sunlight serves as the principal endogenous source for vitamin D synthesis in humans, its efficacy is constrained by multiple factors including geographic latitude, seasonal variation, and degree of skin exposure, making it inadequate for effectively addressing the widespread prevalence of vitamin D deficiency [7]. Although pharmacological supplementation can rapidly correct severe deficiency states, prolonged administration may pose potential health risks. In contrast, food fortification through the addition of vitamin D or its active metabolites to dairy products and cereals, coupled with delivery engineering technologies to enhance bioavailability is widely regarded as the safest and most sustainable supplementation strategy [8], [9]. However, Current vitamin D delivery systems, while demonstrating improved mucoadhesion and in vitro dissolution profiles, fail to address the fundamental transport paradox: Engineered carriers must simultaneously overcome physicochemical barriers while maintaining biological compatibility with endogenous absorption machinery. This critical gap underscores the urgent need for engineering solutions that synergistically optimize carrier design parameters and nutrient-transport pathway modulation.
Contemporary strategies for enhancing vitamin D bioavailability predominantly focus on three engineering dimensions:
- (1) Solubility enhancement through physicochemical modulation (pH adjustment, ultrasonication, ultra-high-pressure homogenization (UHPH));
- (2) Controlled-release nanocarriers employing protein-polysaccharide matrices [10];
- (3) Mucopenetrative systems exemplified by self-emulsifying formulations [11].
While these approaches improve in vitro bioaccessibility, they inadequately address the fundamental biological constraints governing transintestinal vitamin D transport. Emerging mechanistic studies reveal that Vitamin D absorption parallels cholesterol trafficking, being tightly regulated by apical membrane transporters and ATP-binding cassette (ABC) efflux pumps [12], [13]. The apical membrane transporters includs the scavenger receptor class B type 1 (SR-B1), cluster determinant 36 (CD36), and Niemann-Pick C1-Like1 (NPC1L1), etc.; and the ABC efflux pumps involves the ABC transporter B1 (ABCB1), ABC transporter G5/G8 (ABCG5/G8) and ABC transporter A1 (ABCA1),etc. [12], [13]. This dual regulatory system creates a biological checkpoint where carrier-released vitamin D must navigate competing uptake/efflux processes - the critical rate-limiting determinant of systemic bioavailability. Current delivery paradigms face an engineering dilemma: Optimizing physicochemical parameters (solubility/mucoadhesion) often compromises biocompatibility with endogenous transport machinery. For instance, while nanoencapsulation enhances luminal stability, excessive particle-protein interactions may inadvertently alter transporter expression patterns. This biological-pharmaceutical interface necessitates a paradigm shift toward transporter-informed carrier design.
Breakthrough research identifies nutritional modulators (such as polyphenols and phytosterols) capable of strategically programming transporter networks. Peroxisome proliferator-activated receptor γ (PPARγ)-activating flavonoids (such as hesperetin, hesperidin, naringenin, and naringin) upregulate SR-B1-mediated uptake [14], while fatty acids (FAs), such as butyric acid, inhibit ABCB1 efflux through histone deacetylase modulation [15], [16]. In addition, rutaecarpine and related alkaloids induce PPARα-mediated upregulation of ABCA1 efflux transporters [15], facilitating vitamin D translocation from enterocytes to lymphatic circulation. Such findings unveil a "nutritional coding" mechanism where specific dietary components can: (1) Reprogram absorption kinetics via transporter expression tuning; (2) Create temporal absorption windows through efflux pump inhibition; (3) Enhance lymphatic trafficking via ABCA1 activation. Building upon this foundation, we propose a novel “Dietary Nutrient-Transporter-Vitamin D Axis” absorption model. This model not only addresses two critical limitations in existing vitamin D absorption research-the superficial investigation of passive diffusion mechanisms and the lack of effective absorption-promoting strategies based on identified protein transport pathways-but also offers three groundbreaking innovations:
- (1) Mechanistic depth. Integration of transporter regulation with dietary nutrient combinations.
- (2) Technical breakthrough. Precision modulation of absorption pathways at the molecular level.
- (3) Translational value. Fundamental resolution of vitamin D’s low absorption rate challenge.
Advanced co-delivery platforms now enable synergistic carrier construction. For example, quercetin (Que) was encapsulated within FA-sodium caseinate co-assemblies through self-assembly [17]; microfluidic-engineered Pickering emulsions co-encapsulate curcumin (Cur) with β-carotene [18]. In addition, delivery systems based on novel processing technologies, such as electrostatic spinning (ESP) and thin-film hydration, also offer the possibility of co-encapsulating vitamin D with dietary components that promote absorption through specific transport protein pathways.
Existing reviews predominantly catalog material innovations [19], [20] or system-specific optimizations [8], [21], [22], [23] lacking integrative analysis of biological transport barriers. This review pioneers a transporter-adaptive delivery framework that: (1) Deciphers molecular crosstalk between nutritional modulators and vitamin D transportome; (2) Establishes design principles for "biologically synchronized" carriers; (3) Proposes a dual-optimization strategy, namely nutrient-mediated transporter programming and carrier engineering for target-compatible release. This biointerface-focused approach transcends conventional formulation science, offering effective solutions to the challenge of oral vitamin D delivery. By aligning pharmaceutical engineering with molecular nutrition principles, we chart new pathways for precision delivery systems that respect intestinal absorption biology. Compared with traditional vitamin D supplementation strategies, this approach offers significant synergistic benefits in surpassing the intestinal absorption ceiling of vitamin D, optimizing conventional supplementation methods, and providing additional nutritional benefits through compound formulation. Furthermore, by integrating molecular mechanisms of transporter-targeted regulation with advanced carrier material technologies, this strategy represents a significant paradigm shift in the field of vitamin D nutritional intervention.
Section snippets
The mechanism behind intestinal vitamin D absorption
Intestinal vitamin D absorption involves several key steps, including vitamin D release, micellization, and transmembrane transport, as well as celiac particle formation and release. Vitamin D is released from the food matrix to form mixed micelles with phospholipids, cholesterol, bile salts, and lipid digestion products, which are digested in the gastrointestinal tract, recognized by intestinal epithelial cells, and transported [24], [25], [26]. Vitamin D is similarly compatible with the . . . . .
Different dietary nutrients combined with vitamin D regulate the absorption of vitamin D
Some dietary nutrients can regulate the transport pathways of vitamin D through intestinal epithelial receptor proteins, thereby affecting its intestinal absorption. Table 1 summarizes the effect of nutrients on transport proteins. Combining different dietary nutrients with vitamin D to promote or inhibit its protein transport can precisely regulate intestinal VD absorption and improve its bioavailability (Fig. 2).
Strategies for constructing functionalized carriers based on the regulatory pathways of transport protein
The strategic combination of dietary nutrients with vitamin D enables molecular level modulation of its intestinal absorption. Integrating this transporter mediated absorption paradigm with carrier design yields functionalized delivery systems that significantly enhance vitamin D’s nutritional efficacy.
Applications and outlook
Modern molecular nutritional research involving intestinal vitamin D absorption has yielded several primary findings:
- (1) Transport proteins strictly regulate intestinal epithelial cell vitamin D absorption.
- (2) Dietary nutrients can modulate transporter-based VD absorption pathways.
- (3) A pro-absorptive effect can be achieved by regulating functional factors within the transport protein pathways.
Therefore, enhancing the intestinal absorption and bioavailability of vitamin D by regulating . . . .
Conclusion
Vitamin D is closely regulated by transport proteins during trans-intestinal epithelial cell absorption, limiting its intestinal absorption and bioavailability. Modern molecular nutritional studies have revealed that some dietary nutrients can influence the intestinal absorption of vitamin D by modulating the transport protein pathway. Therefore, this work proposes incorporating dietary nutrients that promote apical uptake and basolateral transporter-mediated efflux pathways while inhibiting . . . .
A few of the references
- E. Reboul -Proteins involved in fat-soluble vitamin and carotenoid transport across the intestinal cells: new insights from the past decade -Prog. Lipid Res. (2023)
- Y. Chen et al. – Butyrate from pectin fermentation inhibits intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein e-deficient mice – J. Nutr. Biochem. (2018)
- A. Goncalves et al. – Pinoresinol of olive oil decreases vitamin D intestinal absorption – Food Chem. (2016)
- A. Goncalves et al. – Fat-soluble vitamin intestinal absorption: absorption sites in the intestine and interactions for absorption Food Chem. (2015)
Study ignores: poor health of gut, liver, or kidneys; topical Vitamin D; genes that enhance/restrict/destroy Vitamin D; etc.
Other ways to get Vitamin D into your cells
-
- Sublingual vitamin D
- Nanoemulsion Vitamin D is faster and better - many studies
- Topical Vitamin D
- Injection
See also VitaminDWiki
- Some supplements: Vitamin D, Vitamin K, Omega-3, etc. must be taken with fatty meals (there are other forms)
- Water-dispersible forms of vitamins A, D, E and K are better
- Cooked dried beans or peas (pulses) reduce uptake of fat soluble vitamins
- Genetics
- Reasons for low response to vitamin D
- low Mg, low Omega-3, low Boron, high vitamin A, high Omega-3, high age ...