Abstract

Cistanche deserticola is a valuable medicine–food homologous botanical, whose primary bioactive constituents are phenylethanoid glycosides (PhGs), including echinacoside (ECH) and acteoside (ACT). PhGs demonstrate diverse bioactivities-such as antioxidant activity, neuroprotection, anti‑cancer potential, hepatoprotection, and cognitive function support-yet their clinical and product efficacy are often limited by low oral bioavailability. Current evidence indicates that low bioavailability mainly results from strong polarity, limited intestinal permeability, and rapid metabolic clearance.

 

 

Cistanche Extract In The Market

Get more details

Supportive Service Of Wecistanche-For more details about cooperation
Email:wallence.suen@wecistanche.com

 

 

Across multiple studies, common in vivo metabolic features of PhGs include esterase‑mediated hydrolysis, gut microbiota‑driven biotransformation, and phase‑II conjugation (notably glucuronidation), which collectively determine their systemic stability and duration of effect. Delivery technologies-such as liposomes (Lip), solid lipid nanoparticles (SLN), and polymeric nanoparticles (NPs)-can substantially improve the stability and apparent solubility of PhGs. For product developers, nano‑enabled encapsulation with protective and controlled‑release functions offers a practical strategy to reduce hydrolysis, enhance membrane transport, and extend residence time, thereby improving both absorption and pharmacodynamic performance. Achieving spatial and temporal control of release is considered a key direction to unlock the functional potential and application value of PhGs. This review integrates chemical, biological, and pharmaceutic evidence to clarify key mechanisms that govern PhG performance in vivo and to propose optimization patterns that can guide the development of PhG‑based functional foods and clinical candidates.

 

Keywords

Cistanche; phenylethanoid glycosides (PhGs); echinacoside (ECH); acteoside (ACT); bioactivity; bioavailability; delivery systems

 

Introduction

Background: botanical source and traditional use

Cistanche deserticola Ma (family Orobanchaceae) is a root‑parasitic plant that primarily parasitizes the roots and rhizomes of host plants such as Tamarix spp. and Haloxylon spp. It is widely distributed in arid and saline‑alkali regions of Inner Mongolia, Xinjiang, and Qinghai, and has also been cultivated in saline‑alkali areas such as Dongying and Weifang (Shandong Province) in recent years [1]. With a long history of medicinal use and high medicinal value, it is often referred to as "desert ginseng" [2]. It was first classified as a "top‑grade" herb in Shennong Bencao Jing, and later included in classical materia medica such as Bencao Shiyi and Bencao Beiyao [3]. In traditional Chinese medicine (TCM), Cistanche is described as sweet and salty in taste and warm in nature, entering the Kidney and Large Intestine meridians; it is used to "tonify kidney yang," enrich essence and blood, and moisten the intestines for constipation relief, with traditional indications including kidney‑yang deficiency, impotence/infertility, soreness/weakness of the waist and knees, and constipation due to intestinal dryness [4].

In China, research has focused on four commonly studied botanical sources: Cistanche deserticola, Cistanche tubulosa (Schenk) Wight, Cistanche salsa G. Beck, and Cistanche sinensis G. Beck [5]. The medicinal part is the fleshy stem with scale leaves, typically used after drying and slicing. Notably, in 2023, C. deserticola was officially included in the list of substances used as both medicine and food ("medicine–food homologous" catalog), which substantially expands opportunities for resource development and downstream applications [text source].

Bioactive constituents and quality markers relevant to product development

Modern phytochemical studies have identified multiple classes of constituents from Cistanche species, including primary metabolites (e.g., sugars, organic acids) and secondary metabolites such as phenylethanoid glycosides, iridoids, and lignans [6]. Among these, phenylethanoid glycosides (PhGs) are the most representative and abundant bioactives in Cistanche. Echinacoside (ECH) and acteoside (ACT) are used as quality control markers in the 2025 edition of the Pharmacopoeia of the People's Republic of China [1], and ECH content can reach approximately 3% in some Cistanche materials [7]. PhGs are water‑soluble natural glycosides with broad biological activities, including antioxidant activity, cognitive impairment improvement, anti‑cancer effects, and hepatoprotection [7–9]. Accordingly, a large body of experimental research has focused on their pharmacological properties. For instance, ACT has been reported to exert immunomodulatory effects in an MPTP‑induced mouse model of Parkinson's disease [10]; in Alzheimer's disease (AD)‑related models, Cistanche PhG extracts also show neuroprotective effects in PC12 cells [11], supporting potential applications in neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, and ischemic brain injury.

The core bottleneck: oral delivery and systemic exposure

As a medicine–food homologous ingredient, Cistanche bioactives are primarily administered orally. However, to exert effects at target sites, orally consumed actives must overcome multiple physiological barriers, including the harsh and variable gastrointestinal environment, limited intestinal epithelial uptake, hepatic first‑pass metabolism, and additional distribution/retention/release constraints at the target organ [12]. Despite robust bioactivity in vitro and in vivo models, PhGs often exhibit poor intestinal absorption and low overall bioavailability after oral dosing. As a result, systemic plasma concentrations can be very low, and a substantial fraction may be excreted in prototype form, limiting in‑body exposure and therapeutic potential [13–15].

Opportunity for formulation and delivery systems (US‑market framing)

With advances in oral absorption science and food/pharmaceutical formulation technologies, strategies to improve oral bioavailability have expanded rapidly. Delivery systems can enhance stability in processing/storage/transport (e.g., protection from light, heat, and oxidation) and can also protect PhGs from degradation by light, oxygen, and digestive enzymes while enabling targeted release and absorption enhancement. Consequently, encapsulation‑based delivery has become a key approach in functional food and dietary supplement R&D for improving the bioavailability of PhGs. This review focuses on (i) physiological functions, gastrointestinal absorption characteristics, and food‑grade encapsulation strategies for ECH and ACT, (ii) progress in PhG delivery systems, and (iii) future R&D directions aimed at improving bioavailability and translational potential, thereby providing a practical evidence base for ingredient development and industrial application.

 

1. Structure Characteristics and Bioactivities of Phenylethanoid Glycosides in Cistanche

1.1 Structure characteristics of PhGs in Cistanche

Phenylethanoid glycosides (PhGs) are a class of naturally occurring polyphenolic compounds. Their characteristic structural motif is a hydroxyphenethyl group linked to a caffeoyl or cinnamoyl moiety via glycosidic and/or ester bonds 161616. As the most important active substances in Cistanche, PhGs are also widely distributed in many plant species and are typically water‑soluble glycosides 171717. Structurally, PhGs are commonly described as comprising four parts: the aglycone, a central glucose, rhamnose, and a phthalide‑related moiety (as stated in the source text). In Cistanche, most PhGs share a general scaffold; substitutions frequently include acetyl groups, β‑D‑glucose, α‑L‑rhamnose, caffeoyl, feruloyl, coumaroyl, and 2,3,4‑acetyl‑α‑L‑rhamnose groups. In many cases, the sugar units are glucose and rhamnose: the central sugar directly connected is usually glucose; at the 3‑position of the central glucose, rhamnose is attached in most structures except monosaccharides; in trisaccharide structures, a second glucose is often linked at C6 of the central glucose. In addition, caffeoyl/feruloyl/coumaroyl moieties frequently form an ester bond at the 4‑ or 6‑position of the central glucose.

Using ACT as an example, its structure includes one caffeic acid moiety and one dihydroxyphenethyl residue, which are connected via glycosidic linkage to a trisaccharide (two glucose units and one rhamnose unit). ECH, by contrast, is described as a disaccharide derivative composed of hydrated tyrosol with an α‑L‑rhamnosyl‑(1→3)‑β‑D‑glucoside core (as stated in the source text).

Historically, PhG research can be traced back to the 20th century: Scarpati and colleagues first isolated and identified ACT from Verbascum (mullein) in 1936 181818. Later, in 1950, Viswanathan and colleagues isolated the first PhG compound from a plant source (as stated in the source text) 191919. To date, nearly 500 PhG compounds have been isolated from natural sources 202020.

Since the 1970s, systematic studies have focused on C. deserticola and C. tubulosa. Kobayashi and colleagues reported multiple PhGs, including acteoside (Acteoside) (compound 1), echinacoside (compound 11), salidroside (compound 10), and cistanosides A–F, among others 212121. With continued advances, many additional PhGs have been isolated and identified. One review summarized 22 PhGs isolated from Cistanche plants, including 1 monosaccharide glycoside, 14 disaccharide glycosides, and 7 trisaccharide glycosides 222222. Chen et al. investigated the chemical constituents of a 70% ethanol extract of C. deserticola using LC‑MS combined with xanthine oxidase (XO) inhibition profiling, and identified nine compounds, of which seven were PhGs and two were phenylpropanoid glycosides 232323. Using UPLC‑QQQ‑MS combined with PLS‑DA, Lv et al. compared fresh Cistanche samples parasitizing different host plants and quantitatively analyzed eight PhGs 242424. The source text states that, to date, 55 PhGs with elucidated structures have been summarized for Cistanche species (details referenced in "Figure 1"). Overall, PhGs are among the most representative and structurally diverse chemical constituents of Cistanche, providing a strong foundation for mechanistic pharmacology and product development.

 

1.2 Bioactivities

1.2.1 Antioxidant activity

PhG extracts from Cistanche exhibit strong antioxidant capacity, including scavenging of superoxide anion radicals (O2−_2^-2−​·) and hydroxyl radicals (·OH). Using DPPH and ABTS assays, An et al. evaluated PhGs extracted from Cistanche collected from different hosts and producing areas; results consistently showed good antioxidant activity 252525.

Based on the source text, the antioxidant effects of PhGs are mainly achieved via three routes:

(1) Direct radical quenching and reinforcement of endogenous antioxidant defenses. PhGs can directly quench free radicals and can also increase the activity and expression of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px). These enzymes are regulated by the transcription factor Nrf2 and constitute a central antioxidant defense mechanism 262626.

(2) Reduction of radical generation by interrupting chain reactions. PhGs may reduce free‑radical formation by interfering with radical chain reactions, thereby mitigating oxidative damage 272727. In a rat middle cerebral artery occlusion (MCAO) model, Han et al. reported that salidroside (SAL) alleviated ischemia–reperfusion injury via activation of the Nrf2/ARE pathway 282828.

(3) Lowering lipid peroxidation markers and oxidative stress indices. The PhG monomer ECH can reduce the concentration of malondialdehyde (MDA), a lipid peroxidation product. In a carbon tetrachloride (CCl4_44​)‑induced oxidative stress model, ECH treatment reduced hepatic MDA and restored SOD activity and glutathione (GSH) levels 292929. In a rat colon ischemia–reperfusion (I/R) injury model, intraperitoneal administration of ACT (10 mg/kg) significantly reduced MDA, total oxidant status (TOS), and oxidative stress index (OSI) 303030. ACT has also been reported to attenuate neuroinflammation‑related signaling (as reflected by phosphorylation changes in IκBα, NF‑κB p65, and IKKα+β) in an APP/PS1 Alzheimer's disease mouse model 313131.

Because oxidative stress is a shared pathological driver for many cancers and neurodegenerative diseases, the multi‑target, multi‑pathway antioxidant actions of PhGs may represent a common intervention entry point for these conditions.

Product‑development note (US market): If the intended claim category is "supports antioxidant defenses," formulation strategies that preserve phenolic integrity during processing/storage (light/oxygen control, moisture barrier packaging) and that improve in‑vivo exposure may be crucial for consistency between label dose and physiological effect.

 

1.2.2 Neuroprotective activity

Neuroinflammation is a major pathological mechanism in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. PhGs can exert neuroprotective effects via anti‑inflammatory actions and inhibition of apoptosis pathways 323232.

Cognitive decline is a common clinical feature in neurodegeneration, affecting memory, attention, learning, and decision‑making. Damage to the cholinergic system is closely associated with cognitive impairment. PhGs can inhibit acetylcholinesterase (AChE), increase acetylcholine (ACh) levels, improve cholinergic function, and thereby alleviate cognitive deficits. For example, in an amyloid‑β (Aβ)‑induced Alzheimer's disease model, ECH reportedly improved cognitive function by inhibiting Aβ deposition and modulating cholinergic neurotransmission 333333. In C6 glioma cells pretreated with lipopolysaccharides (LPS) and IFN‑γ, ACT inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase‑2 (COX‑2), suggesting potential application in oxidative stress‑related neurodegenerative contexts 343434.

ECH can also modulate Nrf2/ARE signaling in Parkinson's disease models, activating antioxidant gene expression and mitigating oxidative stress to protect neurons (as stated in the source text). ACT has been reported to influence microglial activation and suppress NLRP3‑related pathways, thereby reducing acute inflammation, neuronal injury, and apoptosis 35–3635–3635–36. In a study evaluating ECH in acute dopaminergic neuron injury, Chen et al. found that ECH prevented reductions in dopamine and its metabolites in rat striatal extracellular fluid, consistent with suppression of oxidative stress‑associated injury processes 373737. In APP transgenic AD mice, Li et al. reported that 3‑month oral administration of SAL reduced IL‑6 and TNF‑α expression, inhibited neuroinflammation, and improved AD‑like learning and memory impairment 383838.

Overall, PhGs may provide neuroprotection via coordinated regulation of neuroinflammation, oxidative stress, and cholinergic neurotransmission, thereby alleviating neuronal damage and cognitive dysfunction.

Product‑development note (US market): For brain‑health positioning, developers should be cautious: (i) human evidence is typically required for strong structure/function claims, (ii) bioavailability limitations and blood–brain barrier delivery are key translational gaps, and (iii) delivery system choice (e.g., intranasal micelles vs oral liposomes) will strongly shape feasibility and claim language.

 

 

 

1.2.3 Anti‑cancer activity

PhGs have demonstrated anti‑cancer potential. Mechanistically, they may induce cell cycle arrest and apoptosis, and inhibit tumor cell proliferation, invasion, and migration 39–4039–4039–40. ACT was described as selectively inducing apoptosis in breast cancer cells via activation of the TLR4/MyD88 pathway, downregulation of NF‑κB, an increased Bax/Bcl‑2 ratio, and increased caspase‑3 activity (as stated in the source text). Dong et al. reported that ECH inhibited growth across several human cancer cell lines (SK‑HEP‑1 hepatoma, MCF‑7 breast cancer, and SW480 colorectal cancer) 414141. Further work indicated that ECH arrested SW480 cells in G1 phase and induced caspase‑3‑dependent apoptosis via a mitochondria‑associated intrinsic pathway 414141. Liu et al. reported that ECH inhibited proliferation, migration, invasion, and angiogenesis of serous ovarian cancer cells and induced apoptosis via downregulation of the PI3K/AKT signaling pathway 424242. In hepatocellular carcinoma (HCC), ECH was reported to inhibit proliferation and promote apoptosis via reducing TREM2 expression in myeloid cells and suppressing PI3K/AKT signaling (as stated in the source text) 434343. SAL has also been reported to inhibit proliferation, migration, and invasion of human colon cancer SW1116 cells by downregulating the JAK2/STAT3 signaling pathway 444444.

Overall, given their multi‑target mechanisms and a generally favorable safety profile in preclinical contexts, PhGs show potential as candidates for oncology‑adjacent research; however, translation to functional foods/dietary supplements requires careful claim framing and compliance.

 

1.2.4 Other activities

The liver is the largest solid organ in the body and plays key roles in detoxification, immune regulation, metabolism, and energy balance 454545. Multiple studies indicate that ECH can protect against various forms of liver injury. ECH can increase SOD, catalase (CAT), and GSH levels, reduce MDA, and inhibit inflammatory cytokines including IL‑1β, IL‑6, and TNF‑α in drug‑ or chemical‑induced liver injury models 464646. Accordingly, PhGs may have potential as hepatoprotective agents.

In the context of aging societies, osteoporosis imposes a growing socioeconomic burden, with postmenopausal women representing a major patient population. Evidence suggests that estrogen deficiency is a key driver of accelerated bone loss during the first decade after menopause 474747. In ovariectomized rats, Li et al. reported that ECH significantly improved bone mineral density, biomechanical properties, and bone microarchitecture, partly mediated by estrogen‑like activity, and that its anti‑osteoporotic effect was superior to icariin (ICA) in the referenced comparison 484848. Mechanistic discussion in the source text suggests that an ortho‑phenolic hydroxyl pattern on the benzoyl ring may be a key structural feature for potency (as stated in the source text). These findings suggest ECH as a potential preventive candidate or lead compound for osteoporosis research.

In addition, PhGs showed inhibitory activity against enzymes relevant to wound healing, including hyaluronidase, elastase, and collagenase. ACT may promote wound healing by increasing hyaluronic acid levels and enhancing wound contraction 494949. PhGs have also been described as having potential value in myocardial ischemia/reperfusion protection, non‑hormonal male reproductive dysfunction, and asthma adjunctive therapy 50–5250–5250–52.

 

2. In Vivo Metabolism and Bioavailability

Bioavailability refers to the rate and extent to which an active substance is absorbed and reaches systemic circulation, reflecting the proportion that enters the bloodstream. For oral administration, bioavailability specifically refers to the fraction of an orally administered compound that is absorbed from the gastrointestinal tract and survives hepatic first‑pass metabolism to reach systemic circulation. For PhGs, low oral absorption, rapid metabolism, and fast elimination collectively lead to poor overall bioavailability. Low oral bioavailability makes it difficult to achieve effective systemic exposure at target sites, thereby limiting the translation of observed bioactivities into consistent in‑vivo effects [53]. Accordingly, in recent years, researchers have explored multiple strategies to improve PhG bioavailability.

2.1 Research progress in pharmacokinetics of PhGs

2.1.1 Analytical methods used in pharmacokinetic studies

Quantification of PhGs in biological samples has primarily relied on HPLC‑UV and LC‑MS/MS methods. Jia et al. developed an HPLC‑UV method for determination of ECH in rat plasma. Rat plasma was treated by trichloroacetic acid precipitation, and the supernatant was directly injected for analysis. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) were 9 and 29.2 ng/mL, respectively, and the method was successfully applied to pharmacokinetic studies of ECH [54].

Wei et al. established an HPLC method to determine ECH concentrations in plasma and brain tissue from rats with cerebral ischemia. Methanol was used as the precipitating agent, chlorogenic acid served as the internal standard, and separation was performed on a C18 column with isocratic elution using methanol–0.3% phosphoric acid (28.5:71.5), with detection at 330 nm. The method showed good specificity; the LLOQ for ECH in both plasma and brain tissue was 8.33 μg/L. The linear ranges were 8.33–416 μg/L (plasma) and 8.33–166 ng/g (brain tissue). Average extraction recoveries were 80–89%, and samples were stable at −4 °C for 12 h. The method was suitable for quantification of ECH in rat plasma and brain tissue and for pharmacokinetic studies [55].

Wang established an HPLC‑QTOF‑MS method to quantify ACT and its metabolite caffeic acid in rat plasma [56]. Overall, chromatography–mass spectrometry is a core analytical approach for PhGs. LC‑MS/MS, due to high sensitivity (often at ng levels), has become the preferred method for measuring PhGs (e.g., ECH and ACT) in biological matrices, while HPLC‑UV remains a cost‑effective alternative for routine pharmacokinetic studies.

Product‑development note (US market): When planning human studies or quality substantiation, LC‑MS/MS methods that can distinguish parent compounds from major conjugates/metabolites are particularly important, because the "active exposure" may be driven by metabolites rather than the intact glycosides.

2.1.2 Current status of pharmacokinetic findings

To date, research on ECH metabolism and its bioactivity remains relatively limited. The source text summarizes pharmacokinetic results of different PhGs across models ("Table 1"). Notably, bioavailability can differ substantially across animal species; for example, ACT bioavailability in beagle dogs is reported to be significantly lower than that in rats. For oral administration, AUC and Cmax⁡C_{\max}Cmax​ are generally low and absorption is slow, strongly influenced by intestinal absorption and hepatic metabolism. Species differences and disease models can further alter absorption efficiency.

After oral administration of ECH at 100 mg/kg in rats, the absolute bioavailability was reported as only 0.83% [54]. The oral bioavailability of ACT in rats was reported as only 0.12% [57], indicating extremely limited absorption. By analyzing plasma, urine, and feces samples after dosing in rats and beagle dogs, 21 metabolites were identified; among them, 3,4‑dihydroxyphenethyl alcohol and its sulfate conjugate showed the highest responses [58] and were present across gastrointestinal tract, plasma, and excreta samples. Some literature suggests that 3,4‑dihydroxyphenethyl alcohol may have activity similar to ECH [59]. Thus, it can be preliminarily inferred that 3,4‑dihydroxyphenethyl alcohol and its sulfate conjugate may represent key material bases contributing to the in‑vivo effects after oral ECH administration.

PhGs are prone to hydrolysis within the intestinal lumen, generating phenylethanoid derivatives and causing rapid decline of parent compound concentration. Even when absorbed into the portal system, they undergo extensive first‑pass metabolism in the liver, such as sulfation and glucuronidation. The relatively high plasma level of the sulfate conjugate of 3,4‑dihydroxyphenethyl alcohol suggests that first‑pass metabolism is dominant in PhG pharmacokinetics. Therefore, low bioavailability of PhGs is mainly attributable to low intestinal absorption efficiency and extensive first‑pass metabolism. This apparent "absorption–activity mismatch" is a recurring challenge in translating botanically derived actives into effective oral products.

 

2.2 Absorption and metabolism of PhGs in vivo

Oral administration is the most common route for foods and dietary supplements. After ingestion, actives must pass multiple steps before reaching target sites: exposure to gastric acid, digestive enzymes, and gut microbiota; transport across the intestinal epithelium into systemic circulation; and distribution to target tissues where retention and release can become additional bottlenecks [12]. The rate and extent of PhG absorption in the gastrointestinal tract are directly influenced by chemical structure. Although PhGs show promising biological effects, poor intestinal absorption, low bioavailability, and susceptibility to intestinal and hepatic first‑pass effects lead to unstable efficacy [68]. Further studies indicate that ECH may undergo various hydrolysis reactions in the gastrointestinal tract and generate secondary metabolites before absorption into blood [69]. This suggests that the oral bioactivity of PhGs may not be solely derived from parent compounds; metabolites may also play significant roles in overall effects (referenced as "Figure 2" in the source text).

2.2.1 Absorption patterns of PhGs

Systemic effects of natural PhGs depend on bioavailability and the ability to cross gastrointestinal barriers. However, their practical potential is constrained by multiple limitations, among which limited intestinal absorption is a key factor driving low ECH bioavailability [70]. In addition, the human intestine expresses multiple efflux transporters, including P‑glycoprotein (P‑gp) and multidrug resistance‑associated proteins (MRPs) within the ATP‑binding cassette (ABC) transporter superfamily [71]. The Caco‑2 cell model is widely used as an in‑vitro small intestinal absorption model to study absorption characteristics of PhG‑enriched extracts. According to the source text, results indicate that ECH and ACT absorption is not limited by the P‑gp efflux pump or MRP2 protein [72]. Using a Caco‑2 monolayer, Gao et al. further demonstrated that a PhG‑rich extract from C. deserticola and its major monomer ECH undergo transepithelial transport mainly by passive diffusion, with apparent permeability coefficients on the order of 10−710^{-7}10−7 cm/s [73]. ECH therefore exhibits limited membrane permeability and substantial presystemic metabolism, which may be major reasons for reduced oral bioavailability in rats [74].

Both in‑vitro and in‑vivo evidence supports clear biological activity of PhGs, yet efficient absorption remains difficult; large amounts may be metabolized into smaller molecules in the gastrointestinal tract or excreted before entering systemic circulation. Therefore, advanced delivery systems are often proposed to (i) physically encapsulate or chemically protect PhGs from gastrointestinal degradation, and (ii) extend residence time and promote transmembrane transport via targeting and controlled release, thereby delivering sufficient amounts of active ingredients and/or key metabolites to target sites.

Product‑development note (US market): For oral supplements, this section implies that improving "exposure" may require (a) protecting ester/glycosidic linkages from early hydrolysis, (b) increasing apparent permeability, and (c) deciding whether to target delivery of parent glycosides or to leverage/standardize key metabolites (a more complex but potentially more consistent strategy).

2.2.2 Metabolic pathways of PhGs in vivo

Key factors influencing PhG absorption include the type, substitution position, and number of glycosyl groups. Huo et al. studied absorption, distribution, and excretion of ACT in rats and concluded that its absorption followed first‑order kinetics. ACT concentrations were highest in intestine and lung, followed by stomach and muscle, with small amounts distributed to other tissues; it was mainly eliminated through metabolism [75]. Li et al. used an everted intestinal sac model and an in‑vivo single‑pass intestinal perfusion model to study ECH intestinal absorption. They found that absorption occurred primarily in the small intestine, but the maximum intestinal permeability was only 3.23×10−63.23 \times 10^{-6}3.23×10−6 cm/s, categorizing ECH as a poorly absorbed compound [76]. Lei et al. used reversed‑phase HPLC with ECH and related compounds as markers to study gastrointestinal metabolism of PhGs in dogs and found that major metabolism occurred in the colorectum [77].

Gastrointestinal metabolism refers to chemical degradation under digestive enzymes and/or biodegradation mediated by microorganisms. Enzymes related to such metabolism include those secreted by the stomach, pancreas, and small intestinal cells, as well as enzymes from the intestinal microbiota [78]. PhGs' broad bioactivities have stimulated extensive studies on in‑vivo and in‑vitro metabolism. Guo et al. co‑incubated ECH and ACT with human gut microbiota for 36 h and identified metabolites including hydroxytyrosol, caffeic acid, and 3‑hydroxyphenylpropionic acid [79]. ECH comprises four chemical components in its structure: caffeic acid, hydroxytyrosol, rhamnose, and glucose. The ester bond in its molecule is easily cleaved under harsh conditions such as strong acid or strong base, leading to degradation (as stated in the source text).

Ma et al. analyzed feces after oral ECH administration in rats using HPLC‑MS and mainly detected four glycosidic hydrolysis products: acteoside, decaffeoyl‑acteoside, "huangdahua yangdi huang glycoside" (as named in the source text), and 3,4‑dihydroxyphenethyl alcohol; parent drug was also detected, indicating incomplete absorption of ECH in the intestine [80]. In rat gastrointestinal tract, ECH was described as sequentially losing glycosyl groups and caffeoyl groups, producing the above metabolites. After oral administration of ACT at 100 mg/kg in rats, ACT was rapidly metabolized via sulfation, glucuronidation, oxidation, and methyl conjugation, yielding 35 metabolites, including six degradation by‑products and 19 parent‑related metabolites [81]. ECH is described as first undergoing extensive hydrolysis to form ACT, and then further degrading to intermediate products such as caffeic acid and hydroxytyrosol. For SAL, major metabolic pathways include glucuronidation, acetylation, sulfation, and methylation, indicating extensive phase‑I and phase‑II metabolism in rats; excretion occurs mainly via urine, feces, and bile [82].

In summary, low oral bioavailability of PhGs arises from multiple factors. First, labile ester and glycosidic bonds are susceptible to cleavage under gastric acid, digestive enzymes, and microbiota enzymes, resulting in significant luminal metabolism. ACT undergoes rapid sulfation, glucuronidation, oxidation, and methyl conjugation to yield multiple metabolites; ECH is often hydrolyzed to ACT and then further to smaller molecules such as hydroxytyrosol, caffeic acid, and 3‑hydroxyphenylpropionic acid. Detection of both parent compounds and multiple hydrolysis products in feces indicates prominent luminal degradation and incomplete absorption. In Caco‑2 models, transepithelial transport occurs mainly by passive diffusion but with limited efficiency. In the liver, major transformations include glucuronidation, sulfation, and hydrolysis; the resulting conjugates are readily eliminated via bile or urine.

 

3. Strategies to Improve Bioavailability Using Delivery Systems

A delivery system is a technology that controls the distribution of active substances in the body across three dimensions-space, time, and dose. The goal is to release an appropriate amount of active ingredient at the right time and in the right location to improve utilization efficiency, enhance efficacy, and reduce toxicity and adverse effects. For PhGs, practical value is strongly dependent on structural stability and bioavailability; these factors also limit real‑world manufacturing and application [83]. Therefore, encapsulating PhGs within delivery systems can enhance isolation from external stressors (e.g., light, oxygen), reduce degradation during processing, storage, and transport, and enable site‑specific release in vivo, thereby improving bioavailability [84].

3.1 Carrier types and mechanisms

Common delivery systems include emulsions (e.g., nanoemulsions, multilayer emulsions, and Pickering emulsions), liposomes (Lip), nanoparticles, and microcapsules. Liposomes and solid lipid nanoparticles (SLN) are bilayer carriers composed of phospholipids and cholesterol. Liposomes can have both lipophilic and hydrophilic compartments, allowing loading and release of water‑soluble, lipophilic, and amphiphilic actives. With good biocompatibility, liposomes can effectively modulate release rates of encapsulated actives [85]. Active substances can also be adsorbed onto or conjugated to nanoparticle surfaces. As a newer delivery platform, nanoparticles can provide targeting and altered in‑vivo distribution and can modulate release rates to improve bioavailability. Their advantages include high permeability, good stability, and ease of surface modification.

Nanoparticles can effectively enhance bioavailability. Surface modification may reduce uptake by macrophages and alter particle distribution. However, practical applications of SLNs still face challenges such as limited drug loading, early burst release, and potential gelation [86]. In addition, nanosystems often require high‑activity emulsifiers; excessive use may raise food‑safety concerns. Nanoparticles may alter normal absorption pathways and interfere with absorption, distribution, metabolism, and excretion (ADME), creating uncertain biological effects [87]. During preparation and pretreatment, some sensitive compounds may undergo structural changes, resulting in reduced bioactivity [88]. The source text notes that "Table 2" summarizes delivery systems constructed for different PhGs.

Product‑development note (US market): For dietary supplements, "food‑grade" excipients, scalable processes, oxidative stability, and batch‑to‑batch consistency are often as important as improving AUC in animals. A practical development plan typically integrates (i) excipient justification/safety, (ii) stability‑indicating assays, and (iii) a clear human‑relevant rationale (e.g., exposure–response logic or biomarker endpoints).

3.1.1 Liposomal delivery of PhGs

Liposomes can encapsulate actives that are poorly soluble in water or have undesirable taste/odor, and they can fuse with cell membranes to improve bioavailability. As a promising transport system for plant bioactives, liposomes are widely used in functional foods, pharmaceuticals, chemicals, and consumer products. Despite broad research, limitations remain, including difficulty controlling release rates, low encapsulation efficiency [89], and instability with precipitation during storage, which constrain industrial application.

Li et al. prepared an ECH–phospholipid complex (PHY) via solvent evaporation, and characterized it by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Results suggested weak interactions between ECH and phospholipids. This complex significantly promoted ECH absorption in rats and improved bioavailability [68].

Isacchi et al. prepared ACT liposomes using thin‑film evaporation with phosphatidyl 90G (P90G), cholesterol, and ACT. The resulting liposomes had an average particle size of ~120 nm and an encapsulation efficiency of 30%; ACT release was 82.28 ± 1.79%, suggesting the system could effectively suppress ACT hydrolysis and improve stability. In a rat chronic constriction injury model, the liposomal group showed more sustained analgesic effects than free ACT [90].

Zhou et al. prepared liposomes via ethanol injection and coated ACT liposomes with chitosan. ACT liposomes (ACT‑Lip) were spherical, and relative bioavailability reportedly increased to 217.62%. After encapsulation into chitosan‑modified liposomes (Cs‑Lip), key parameters improved. Compared with ACT‑Lip, ACT‑CS‑Lip showed lower in‑vivo release rate and improved storage stability [91].

Ou et al. constructed ANG‑modified ECH liposomes. By leveraging high affinity of ANG for the LRP1 receptor, the liposomes could cross the blood–brain barrier (BBB) via receptor‑mediated transcytosis, increasing ECH distribution in the brain [92].

Overall, liposomes-being relatively mature carriers-can improve PhG bioavailability by reducing degradative exposure and enabling controlled release. Surface modification may reduce plasma protein binding, delay macrophage uptake, and enhance targeting. However, many studies focus on preparation and physicochemical characterization, while systematic investigation of in‑vivo mechanisms and key targeting pathways remains limited.

 

3.1.2 Solid lipid nanoparticles and related lipid/polymer systems

Solid lipid nanoparticles are an important lipid carrier system developed after liposomes. Beyond liposomes and SLNs, polymeric and self‑emulsifying nanoparticle systems also show strong potential for directed delivery of bioactives. By combining advantages of emulsions and polymeric nanoparticles, they are widely used to enhance stability and targeting.

Chen et al. investigated how auxiliary materials affect ECH‑loaded SLNs. Using glyceryl monostearate as the lipid matrix and lecithin plus Myrj52 as surfactants, they prepared SLNs by an emulsion solidification method. Zeta potential and ultrafiltration were used to assess stability and encapsulation efficiency. As Myrj52 concentration increased, particle size decreased and encapsulation efficiency increased. While ECH was encapsulated, further discussion on cellular uptake and bioavailability was limited [93].

Xue et al. characterized optimized SLNs and performed in‑vitro evaluation using ocular cells. Results indicated that ECH existed in SLNs as a molecularly dispersed state, and SLNs could deliver ECH to ocular cells, supporting feasibility for ocular delivery [94].

In another study, Xue et al. synthesized chitosan‑polyethylene glycol‑polylactic acid (mPEG‑PLA) nanoparticles and co‑loaded ACT, plasmid DNA (pDNA), and nerve growth factor (NGF) to form a nanomicelle complex (APPDN) with low toxicity and biodegradability. In an MPTP‑induced Parkinson's disease mouse model, APPDNs showed clear neuroprotective effects [95].

Qi et al. constructed ECH‑loaded micelles (PP‑E micelles) based on an amphiphilic block copolymer containing poly(carboxybetaine methacrylate) (PCBMA) and phenylboronic acid‑modified poly(dimethylaminoethyl methacrylate) (PBA‑PDAMA). These micelles could recognize betaine‑GABA transporter 1 (BGT‑1) in nasal mucosa and thereby cross the epithelium through submucosal olfactory and trigeminal pathways to accumulate in the hippocampus, greatly improving ECH delivery efficiency [96–97].

Compared with liposomes, solid lipid and micellar carriers often exhibit better physical stability, but surface modification can be more challenging and active targeting may be weaker. Nonetheless, SLNs can markedly improve physicochemical stability and barrier‑crossing efficiency, enabling multi‑organ targeting (e.g., eye and brain) and providing a potentially scalable platform for clinical translation of PhGs.

 

3.1.3 Nanoparticle‑based delivery strategies (polymeric NPs and SNEDDS)

In addition to liposomes and SLNs, polymeric nanoparticles and self‑nanoemulsifying drug delivery systems (SNEDDS) show considerable potential for directed delivery.

Su et al. used poly(lactic‑co‑glycolic acid) (PLGA) as a carrier and prepared ECH nanoparticles via a multiple emulsion–solvent evaporation method. Early‑stage single‑factor experiments evaluated PLGA and poloxamer 188 (F68) concentration and the internal aqueous phase/oil phase volume ratio. When PLGA concentration was 5%, corresponding F68 and internal aqueous/oil phase ratios were 2.57% and 0.86%, and the ECH nanoparticle size approximated the theoretical target. Transmission electron microscopy showed spherical particles with smooth surfaces and uniform size distribution. In‑vitro release testing indicated sustained release behavior [98].

Kalantari et al. prepared different self‑emulsifying combinations using water/oil dilution and evaluated SNEDDS to protect a Plantago lanceolata extract containing ACT. Compared with unencapsulated extract, SNEDDS enhanced free‑radical scavenging activity. Cytotoxicity, dissolution, and related tests suggested that the SNEDDS formulation could provide stable, efficient, and safe delivery of natural actives (as described in the cited work) [99].

Han et al. synthesized ECH‑loaded PLGA nanoparticles via double emulsion and modified the nanoparticle surface with folic acid to enable specific recognition of folate receptors on hepatocellular carcinoma cells. The system showed pH responsiveness under acidic conditions, reduced ECH metabolism and inactivation in non‑target tissues, improved stability reaching the tumor site, and thereby improved bioavailability [100]. Nanoparticles modified with targeting ligands (e.g., folate, antibody fragments) can achieve organ/tumor enrichment through receptor‑mediated endocytosis-particularly relevant for BBB or blood–ocular barrier targeting. While multiple delivery systems have improved PhG bioavailability, systematic evaluation of in‑vivo safety, intestinal transport mechanisms, and efficacy remains insufficient and requires further study.

 

3.1.4 Emerging delivery systems and design principles

As polyphenolic substances, PhGs have amphiphilic features and can align well with carrier material properties used in polyphenol delivery systems. Although current polyphenol delivery research often focuses on phenolic acids, the principles and methods are generally applicable to PhGs, providing strong theoretical and technical support for systematically improving oral bioavailability.

Prior work indicates that biopolymers can significantly improve physicochemical properties of encapsulated bioactives [101]. Many studies encapsulate phenolic acids into nanofibers to expand functional applications. For example, β‑cyclodextrin (CD) and its derivatives have been used to encapsulate phenolic acids and then embed them into polylactic acid (PLA) nanofibers. Natural and synthetic materials-such as gelatin, chitosan, PLA, and poly(N‑vinylpyrrolidone)-provide options for efficient encapsulation of phenolic acids into nanofibers, improving flavor and enhancing bioavailability and half‑life under in‑vitro/in‑vivo conditions.

In addition to organic materials, inorganic materials are also widely applied in delivery systems. One study reported one‑step coordination self‑assembly to construct Zn2+^{2+}2+–polyphenol–polypeptide nanocomplexes, achieving efficient, low‑toxicity, non‑antibiotic bacterial eradication in protein environments [102]. Another study reported that grafting phenolic acids onto silica nanoparticle surfaces not only enhanced antioxidant effects but also enabled nanoparticle reuse after simple washing [103]. Additional work has grafted phenolic acids onto polymers such as chitosan, hyaluronic acid, and gelatin to modify polymer properties, improve stability, and facilitate delivery [104].

With the development of intelligent delivery systems, natural polyphenols are increasingly used not only as therapeutic agents but also as functional building blocks for constructing new delivery platforms. Hydroxyl groups can act as hydrogen‑bond donors or acceptors, promoting interactions between polyphenols and other bioactives or carrier materials. Meanwhile, aromatic rings serve as hydrophobic units that enhance hydrophobicity of composite systems, synergistically supporting delivery system construction and functional optimization. Beyond biological effects, polyphenols are increasingly integrated into multifunctional composite systems by combining with proteins [105], metal ions [106], polymers [107], and nucleic acids [108]. Reports indicate that polyphenols can serve as carrier components and protect nanoparticle structural integrity and the bioactivity of loaded interventions [103,109]. These emerging principles and methods may inform future PhG delivery research, enabling systematic improvement of bioavailability and functional performance.

Summary of Section 3: Delivery systems can markedly improve PhG bioavailability. Liposomes, SLNs, and nanoparticles enhance protection, controlled release, and targeting, overcoming key bottlenecks such as poor gastrointestinal absorption and low stability. Emerging systems (polymer nanofibers, inorganic composites, and polyphenol–biomolecule composites) further broaden application possibilities by improving solubility, enhancing targeting, and reducing degradation. Future work should optimize carrier stability, safety, and scalable manufacturing to support broader use in food and medical contexts.
 

4. Outlook

With continued research progress, applications of PhGs and their delivery systems in the food and nutrition space are expanding, and safety has become a key focus. According to the source text, an acute toxicity study reported that no mice died within 14 days after continuous intragastric administration, and average body weight increased by more than 50%. The maximum tolerated dose (MTD) of Cistanche PhG extract in mice was reported as 119.46 g/kg, corresponding to 882 times the adult dosage, indicating very low toxicity and favorable preclinical safety [110]. Another acute toxicity study reported that within the dose range of 100 mg/mL, a PhG nanoemulsion showed no toxicity; intranasal administration produced no obvious adverse effects on nasal mucosa or major organs, further supporting safety of the delivery system [111].

However, existing delivery systems still face important challenges. For example, different standards and models are used to evaluate physicochemical properties and bioavailability, resulting in limited comparability and sometimes poor relevance to specific application goals. In addition, some PhGs may themselves inhibit or induce transporters or metabolic enzymes; changing bioavailability may therefore also alter these functions. Current directed transport of PhGs in delivery systems may not achieve precise localization, which can contribute to reduced absorption and bioavailability.

 

 

As a class of polyphenolic compounds, PhGs have broad chemical, biological, and physiological activities. Nonetheless, poor stability and low bioavailability remain key barriers to deeper application in nutrition and health. This review summarizes major bioactivities, digestion/absorption/metabolism characteristics, and research progress in delivery systems for representative PhGs. Existing evidence indicates that delivery systems can protect PhGs under diverse in‑vitro and in‑vivo conditions and can effectively improve stability and bioavailability. Delivery systems can also enable directed transport and release, facilitating specific therapeutic effects. Similar to many polyphenols, PhGs contain abundant ortho‑ and meta‑hydroxyl groups and hydrophobic aromatic rings, enabling interactions with proteins, metals, and polymers via hydrophobic interactions, hydrophilic interactions, charge transfer, hydrogen bonding, and metal coordination, supporting formation of stable and mature delivery systems and expanding opportunities for innovative delivery platform development [112–114]. Even so, key issues remain, including inconsistent evaluation standards and unclear in‑vivo safety profiles. Future work should further investigate factors and mechanisms that influence PhG bioavailability, absorption, metabolism, and transport, improve safety evaluation, and build high‑performance delivery systems.

 

License / Open‑access statement (as provided in the source text)

© The Author(s) 2026. This is an Open Access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑NoDerivatives 4.0 International License (CC BY‑NC‑ND 4.0): https://creativecommons.org/licenses/by-nc-nd/4.0/.

 

References

 

Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (2025 Edition): Volume I. Beijing: China Medical Science Press; 2025. p. 144.

Lei H, Wang X, Zhang Y, et al. Herba cistanche (Rou Cong Rong): A review of its phytochemistry and pharmacology. Chem Pharm Bull (Tokyo). 2020;68(8):694‑712.

Chen CM, Gazang ZX, Wang J, et al. Research progress on active components and pharmacological mechanisms of Cistanches herba. Chinese Traditional and Herbal Drugs (Zhongcao Yao). 2025;56(12):4464‑4477. [Chinese]

Zhang XY, Yu TY, Zhao LH. Exploration of the clinical application and dosage of desert‑living cistanche. Jilin J Tradit Chin Med (Jilin Zhongyiyao). 2022;42(8):966‑969. [Chinese]

Tu PF, Jiang Y. Update classical literature research on Cistanches Herba. China J Chin Mater Med (Zhongguo Zhongyao Zazhi). 2022;47(20):5670‑5679. [Chinese]

Zhao HT, Xin GX, Guo Y. Research progress on Cistanches Herba as medicine and food homologous traditional Chinese medicine. Chinese Traditional and Herbal Drugs (Zhongcao Yao). 2025;56(9):3316‑3329. [Chinese]

Zhang X, Hao Y. Beneficial effects of echinacoside on diabetic cardiomyopathy in diabetic db/db mice. Drug Des Devel Ther. 2020;14:5575‑5587.

Chuang HW, Wang TY, Huang CC, et al. Echinacoside exhibits antidepressant‑like effects through AMPAR–Akt/ERK–mTOR pathway stimulation and BDNF expression in mice. Chin Med. 2022;17(1):9.

Chen C, Xia B, Tang L, et al. Echinacoside protects against MPTP/MPP+‑induced neurotoxicity via regulating autophagy pathway mediated by Sirt1. Metab Brain Dis. 2019;34(1):203‑212.

Adilai A, Eibubuli (A B B L). Study on the immune regulation of TLR4/NF‑κB signaling pathway mediated by verbascoside in Parkinson's disease model mice [dissertation]. Urumqi: Xinjiang Medical University; 2024. [Chinese]

Kuang R, Sun YG, Deng TL, et al. The protective effect and mechanisms of echinacoside on H2O2‑injured PC12 cells. Chin Pharmacol Bull (Zhongguo Yaolixue Tongbao). 2009;25(4):515‑518. [Chinese]

Niu C, Li Q, Yang LP, et al. Phenylethanoid glycosides from Callicarpa macrophylla Vahl. Phytochem Lett. 2020;38:65‑69.

Zhang M, Ren X, Yue S, et al. Simultaneous quantification of four phenylethanoid glycosides in rat plasma by UPLC‑MS/MS and its application to a pharmacokinetic study of Acanthus ilicifolius herb. Molecules. 2019;24(17):3117.

Tian J, Lin L, Li X, et al. Forsythiaside stability in pretreated rat plasma and its pharmacokinetics after i.v. administration. Anal Methods. 2015;7(5):1809‑1815.

Baidya R, Sarkar B. A systematic review of the traditional uses, chemistry, and curative aptitude of echinacoside‑a phenylethanoid glycoside. Naunyn Schmiedebergs Arch Pharmacol. 2025;398(3):2071‑2106.

Dembitsky VM. Astonishing diversity of natural surfactants: 5. Biologically active glycosides of aromatic metabolites. Lipids. 2005;40(9):869‑900.

Chen T, Gao F, Luo D, et al. Cistanoside A promotes osteogenesis of primary osteoblasts by alleviating apoptosis and activating autophagy through involvement of the Wnt/β‑catenin signal pathway. Ann Transl Med. 2022;10(2):64.

Val'dman AV, Kozlovskaia MM. An experimental study of the spectrum of individual psychotropic activity of clozapine (Leponex). Zh Nevropatol Psikhiatr Im S S Korsakova. 1975;75(11):1710‑1717.

Viswanathan N, Sundararaj BI. Response of the hypothalamic neurosecretory system of the female catfish, Heteropneustes fossilis (Bloch), to hypophysectomy. Acta Anat (Basel). 1975;93(3):376‑386.

Tian XY, Li MX, Lin T, et al. A review on the structure and pharmacological activity of phenylethanoid glycosides. Eur J Med Chem. 2021;209:112563.

Kobayashi H, Yang XW. Study on the chemical composition of the anti‑aging Chinese herbal medicine Cistanche. Information on Traditional Chinese Medicine (Zhongyiyao Xinxi). 1985;(2):31. [Chinese]

Lei L, Song ZH, Tu PF. Advances in research of chemical constituents in plants of Cistanche Hoffing. et Link. Chinese Traditional and Herbal Drugs (Zhongcao Yao). 2003;34(5):92‑95. [Chinese]

Chen X, Deng Z, Huang X, et al. Liquid chromatography–mass spectrometry combined with xanthine oxidase inhibition profiling for identifying the bioactive constituents from Cistanche deserticola. Int J Mass Spectrom. 2018;430:1‑7.

Lv X, Guo YH, Gao PW, et al. Difference of phenylethanol glycosides in fresh Cistanches Herba from 2 hosts based on UPLC‑QQQ‑MS and PLS‑DA analysis. Chin J Mod Appl Pharm (Zhongguo Xiandai Yingyong Yaoxue). 2025;42(9):1463‑1470. [Chinese]

An Q, Guo YH, An FF, et al. Effect of different hosts and producing areas on the active ingredients and antioxidant capacity of Cistanche deserticola. Lishizhen Med Mater Med Res. 2023;34(9):2236‑2239. [Chinese]

Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2‑related factor 2‑dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol. 2008;8(2):71‑85.

Ding Y, Zhang Y, Wang Z, et al. Echinacoside from Cistanche tubulosa ameliorates alcohol‑induced liver injury and oxidative stress by targeting Nrf2. FASEB J. 2023;37(3):e22792.

Han J, Xiao Q, Lin Y, et al. Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2‑related factor 2 pathway. Neural Regen Res. 2015;10(12):1989.

Wu Y, Li L, Wen T, et al. Protective effects of echinacoside on carbon tetrachloride‑induced hepatotoxicity in rats. Toxicology. 2007;232(1):50‑56.

Değer A, Özyiğit F, Koçak F, et al. Corrective effect of verbascoside on histomorphological differences and oxidative stress in colon mucosa of rats in which colon ischemia‑reperfusion injury was induced. Turk J Gastroenterol. 2021;32(7):548‑559.

Chen S, Liu H, Wang S, et al. The neuroprotection of verbascoside in Alzheimer's disease mediated through mitigation of neuroinflammation via blocking NF‑κB‑p65 signaling. Nutrients. 2022;14(7):1417.

Liu XL, Zhou LL, Yang ZJ, et al. Effects of glycosides of Cistanche on cognitive function and synaptic plasticity in SAMP8 mice. Chinese Archives of Traditional Chinese Medicine (Zhonghua Zhongyiyao Xuekan). 2022;40(1):110‑115, 276‑277. [Chinese]

Shiao YJ, Su MH, Lin HC, et al. Echinacoside ameliorates the memory impairment and cholinergic deficit induced by amyloid beta peptides via the inhibition of amyloid deposition and toxicology. Food Funct. 2017;8(6):2283‑2294.

Esposito E, Dal Toso R, Pressi G, et al. Protective effect of verbascoside in activated C6 glioma cells: possible molecular mechanisms. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(1):93‑105.

Zhou H, Zhang C, Huang C. Verbascoside attenuates acute inflammatory injury caused by an intracerebral hemorrhage through the suppression of NLRP3. Neurochem Res. 2021;46(4):770‑777.

Wang JK, Wang LC, Jiang Y, et al. Neuroprotective effects and mechanism of ethanol extract of Cistanche tubulosa against oxygen‑glucose deprivation/reperfusion. China J Chin Mater Med. 2019;44(13):2686‑2690. [Chinese]

Chen H, Jing FC, Li CL, et al. Echinacoside prevents the striatal extracellular levels of monoamine neurotransmitters from diminution in 6‑hydroxydopamine lesion rats. J Ethnopharmacol. 2007;114(3):285‑289.

Li Q, Wang J, Li Y, et al. Neuroprotective effects of salidroside administration in a mouse model of Alzheimer's disease. Mol Med Rep. 2018;17(5):7287‑7292.

Wei J, Zheng Z, Hou X, et al. Echinacoside inhibits colorectal cancer metastasis via modulating the gut microbiota and suppressing the PI3K/AKT signaling pathway. J Ethnopharmacol. 2024;318:116866.

Bian P, Liu C, Hu W, et al. Echinacoside suppresses the progression of breast cancer by downregulating the expression of miR‑4306 and miR‑4508. Integr Cancer Ther. 2021;20:15347354211062639.

Dong L, Yu D, Wu N, et al. Echinacoside induces apoptosis in human SW480 colorectal cancer cells by induction of oxidative DNA damages. Int J Mol Sci. 2015;16(7):14655‑14668.

Liu J, Tang N, Liu N, et al. Echinacoside inhibits the proliferation, migration, invasion and angiogenesis of ovarian cancer cells through PI3K/AKT pathway. J Mol Histol. 2022;53(2):493‑502.

Ye Y, Song Y, Zhuang J, et al. Anticancer effects of echinacoside in hepatocellular carcinoma mouse model and HepG2 cells. J Cell Physiol. 2019;234(2):1880‑1888.

Sun KX, Xia HW, Xia RL. Anticancer effect of salidroside on colon cancer through inhibiting JAK2/STAT3 signaling pathway. Int J Clin Exp Pathol. 2015;8(1):615‑621.

Amin A, Hamza AA. Oxidative stress mediates drug‑induced hepatotoxicity in rats: a possible role of DNA fragmentation. Toxicology. 2005;208(3):367‑375.

Thida M, Li B, Zhang X, et al. Echinacoside alleviates acetaminophen‑induced liver injury by attenuating oxidative stress and inflammatory cytokines in mice. J Appl Biomed. 2021;19(2):105‑112.

Wang X, Zhen L, Zhang G, et al. Osteogenic effects of flavonoid aglycones from an osteoprotective fraction of Drynaria fortunei: an in vitro efficacy study. Phytomedicine. 2011;18(10):868‑872.

Li F, Yang X, Yang Y, et al. Antiosteoporotic activity of echinacoside in ovariectomized rats. Phytomedicine. 2013;20(6):549‑557.

Guragac Dereli FT, Genc Y, Saracoglu I, et al. Enzyme inhibitory assessment of the isolated constituents from Plantago holosteum Scop. Z Naturforsch C. 2020;75(3‑4):121‑128.

Siu AHL, Ko KM. Herba cistanche extract enhances mitochondrial glutathione status and respiration in rat hearts, with possible induction of uncoupling proteins. Pharm Biol. 2010;48(5):512‑517.

Guo L, Xu P, Li Z, et al. Cistanche total glycoside capsule promotes sperm maturation and fertility by activating the NELL2 lumicrine pathway in a male reproductive impairment model. J Ethnopharmacol. 2025;353:120289.

Liu J, Gao J, Xiong A, et al. Exploring Cistanche's therapeutic potential and molecular mechanisms in asthma treatment. Phytomedicine. 2025;136:156265.

Zhou W, Tan X, Shan J, et al. Effect of chito‑oligosaccharide on the intestinal absorptions of phenylethanoid glycosides in Fructus forsythiae extract. Phytomedicine. 2014;21(12):1549‑1558.

Jia C, Shi H, Wu X, et al. Determination of echinacoside in rat serum by reversed‑phase high‑performance liquid chromatography with ultraviolet detection and its application to pharmacokinetics and bioavailability. J Chromatogr B. 2006;844(2):308‑313.

Wei LL, Chen H, Jiang Y, et al. Determination of echinacoside in plasma and brain tissue of cerebral ischemia injury rats by HPLC method. Chin Pharmacol Bull. 2011;27(5):737‑738. [Chinese]

Wang WG. Pharmacokinetic studies of verbascoside in normoxic and hypoxic rats [dissertation]. Lanzhou: Gansu University of Chinese Medicine; 2023. [Chinese]

Wu Y, Lin L, Sung J, et al. Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely‑moving rats using LC–MS/MS. J Chromatogr B. 2006;844(1):89‑95.

Li J, Ge RC, Zheng RL, et al. Antioxidative and chelating activities of phenylpropanoid glycosides from Pedicularis striata. Acta Pharmacol Sin. 2016;18(1):770‑780.

Dai L, Hao HP, Wang YX, et al. Research progress and thinking on pharmacokinetics/pharmacodynamics of echinacoside. Chinese Journal of Clinical Pharmacology and Therapeutics (Zhongguo Linchuang Yaolixue yu Zhiliao Xue). 2010;15(3):342‑349. [Chinese]
 

Zhou J, Zeng P, Sun JB, et al. Application of two‑phase hollow fiber liquid phase microextraction coupled with high‑performance liquid chromatography for the study of the echinacoside pharmacokinetics in Parkinson's disease rat plasma. J Pharm Biomed Anal. 2013;81‑82:27‑33.

Wen Y, Huo S, Zhang W, et al. Pharmacokinetics, biodistribution, excretion and plasma protein binding studies of acteoside in rats. Drug Res (Stuttg). 2015;66(3):148‑153.

Zhang W, Huo SX, Wen YL, et al. Pharmacokinetics of acteoside following single dose intragastric and intravenous administrations in dogs. Chin J Nat Med. 2015;13(8):634‑640.

Huo SX, Gao L, Peng XM, et al. Comparison of pharmacokinetics after administration of acteoside in rats and beagle dogs. Modern Chinese Medicine (Zhongguo Xiandai Zhongyao). 2016;18(10):1273‑1278, 1304. [Chinese]

Zheng YL. Preliminary study on the pharmacokinetics of acteoside and icariin [dissertation]. Tianjin: Tianjin University of Traditional Chinese Medicine; 2021. [Chinese]

Mao Y, Zhang X, Zhang X, et al. Development of an HPLC method for the determination of salidroside in beagle dog plasma after administration of salidroside injection: application to a pharmacokinetics study. J Sep Sci. 2007;30(18):3218‑3222.

Gu HL, Sun RB, Fei F, et al. Salidroside shows a particular pharmacokinetic property in model rats of myocardial ischemia. Chin Herb Med. 2018;10(2):169‑176.

Huang B, Dan XJ, Zhao X, et al. Absolute bioavailability of salidroside in beagle dogs. Journal of Pharmacy Practice (Yaoxue Shijian Zazhi). 2021;39(1):62‑67, 96. [Chinese]

Li F, Yang X, Yang Y, et al. Phospholipid complex as an approach for bioavailability enhancement of echinacoside. Drug Dev Ind Pharm. 2015;41(11):1777‑1784.

Hurst S, Loi CM, Brodfuehrer J, et al. Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans. Expert Opin Drug Metab Toxicol. 2007;3(4):469‑489.

Wu L, Georgiev MI, Cao H, et al. Therapeutic potential of phenylethanoid glycosides: a systematic review. Med Res Rev. 2020;40(6):2605‑2649.

Surampalli G, Nanjwade K, Patil PA. Corroboration of naringin effects on the intestinal absorption and pharmacokinetic behavior of candesartan cilexetil solid dispersions using in‑situ rat models. Drug Dev Ind Pharm. 2015;41(7):1057‑1065.

Tanino T, Nagai N, Funakami Y. Phloridzin‑sensitive transport of echinacoside and acteoside and altered intestinal absorption route after application of Cistanche tubulosa extract. J Pharm Pharmacol. 2015;67(10):1457‑1465.

Gao Y, Zong C, Liu F, et al. Evaluation of the intestinal transport of a phenylethanoid glycoside‑rich extract from Cistanche deserticola across the Caco‑2 cell monolayer model. PLoS One. 2015;10(2):e0116490.

Li Y, Zhou G, Peng Y, et al. Screening and identification of three typical phenylethanoid glycosides metabolites from Cistanches Herba by human intestinal bacteria using UPLC/Q‑TOF‑MS. J Pharm Biomed Anal. 2016;118:167‑176.

Huo SX, Li JM, Gao L, et al. Absorption, distribution and excretion of acteoside in rats. Chinese Journal of Hospital Pharmacy (Zhongguo Yiyuan Yaoxue Zazhi). 2016;36(6):450‑454. [Chinese]

Li F, Shen J, Yang X, et al. Enhancement of absorption and bioavailability of echinacoside by verapamil or clove oil. Drug Des Devel Ther. 2015;9:4685‑4696.

Lei L, Song ZH, Li YZ, et al. Metabolic regulation of phenylethanoid glycosides from Herba Cistanches in dogs' gastrointestinal tract. Acta Pharm Sin. 2001;36(6):432‑435. [Chinese]

Zhang WX, Yang B, Hu YM, et al. Effect of rat intestinal flora in vitro on metabolites of acteoside. China J Chin Mater Med. 2016;41(8):1541‑1545. [Chinese]

Guo Y, Cui Q, Ren S, et al. The hepatoprotective efficacy and biological mechanisms of three phenylethanoid glycosides from Cistanches Herba and their metabolites based on intestinal bacteria and network pharmacology. J Nat Med. 2021;75(4):784‑797.

Ma ZG, Yang ZL, Feng YP, et al. Metabolites of echinacoside in rat feces by HPLC‑MSn. Chinese Journal of Natural Medicines (Zhongguo Tianran Yaowu). 2008;(5):387‑390. [Chinese]

Qi M, Xiong A, Li P, et al. Identification of acteoside and its major metabolites in rat urine by ultra‑performance liquid chromatography combined with electrospray ionization quadrupole time‑of‑flight tandem mass spectrometry. J Chromatogr B. 2013;940:77‑85.

Zhou Y, Liu YP, Wu LN, et al. Study on metabolic pathways of salidroside in rats. Chinese Traditional and Herbal Drugs (Zhongcao Yao). 2018;49(7):1603‑1611. [Chinese]

Chen YL, Sun WQ, Gao YX, et al. Recent progress in food delivery systems for improving bioavailability of phenolic compounds. Food Science (Shipin Kexue). 2020;41(5):323‑330. [Chinese]

Lu W, Kelly AL, Miao S. Emulsion‑based encapsulation and delivery systems for polyphenols. Trends Food Sci Technol. 2016;47:1‑9.

Refuerzo JS, Alexander JF, Leonard F, et al. Liposomes: a nanoscale drug carrying system to prevent indomethacin passage to the fetus in a pregnant mouse model. Am J Obstet Gynecol. 2015;212(4):508.e1‑508.e7.

Song J, Fan X, Shen Q. Daidzein‑loaded nanostructured lipid carriers–PLGA nanofibers for transdermal delivery. Int J Pharm. 2016;501(1‑2):245‑252.

Dasgupta N, Ranjan S, Mundra S, et al. Fabrication of food grade vitamin E nanoemulsion by low energy approach, characterization and its application. Int J Food Prop. 2016;19(3):700‑708.

Sessa M, Balestrieri ML, Ferrari G, et al. Bioavailability of encapsulated resveratrol into nanoemulsion‑based delivery systems. Food Chem. 2014;147:42‑50.

Munin A, Edwards‑Lévy F. Encapsulation of natural polyphenolic compounds: A review. Pharmaceutics. 2011;3(4):793‑829.

Isacchi B, Bergonzi M, Iacopi R, et al. Liposomal formulation to increase stability and prolong antineuropathic activity of verbascoside. Planta Med. 2016;83(5):412‑419.

Zhou F, Xu T, Zhao Y, et al. Chitosan‑coated liposomes as delivery systems for improving the stability and oral bioavailability of acteoside. Food Hydrocolloids. 2018;83:17‑24.

Ou Z, You Y, Yi H, et al. Key lipoprotein receptor targeted echinacoside‑liposomes effective against Parkinson's disease in mice model. Int J Nanomedicine. 2024;19:8463‑8483.

Chen J, Tong L, Liu ZD, et al. Research of prescription screening of echinacoside solid lipid nanoparticles. Journal of Tianjin University of Traditional Chinese Medicine (Tianjin Zhongyiyao Daxue Xuebao). 2015;34(6):353‑356. [Chinese]

Xue ZF, Zhang B, Chen J, et al. Characterization and in‑vitro cellular uptake evaluation of solid lipid nanoparticles loaded with echinacoside. Journal of Tianjin University of Traditional Chinese Medicine (Tianjin Zhongyiyao Daxue Xuebao). 2019;38(3):290‑295. [Chinese]

Xue Y, Wang N, Zeng Z, et al. Neuroprotective effect of chitosan nanoparticle gene delivery system grafted with acteoside (ACT) in Parkinson's disease models. J Mater Sci Technol. 2020;43:197‑207.

Qi F, Liao Y, Ge C, et al. Intranasally delivered echinacoside micelles modulate mitochondrial fusion against postoperative cognitive dysfunction. Adv Funct Mater. 2025;35(41). doi:10.1002/adfm.202505499.

Hu D, Cheng C, Bian Z, et al. The role of echinacoside‑based cross‑linker nanoparticles in the treatment of osteoporosis. PeerJ. 2024;12:e17229.

Su SS, Chen W, Fang H, et al. Formula optimization of echinacoside‑loaded PLGA nanoparticles by Box–Behnken design and response surface method. Chinese Journal of New Drugs (Zhongguo Xinyao Zazhi). 2016;25(9):1069‑1074. [Chinese]

Kalantari A, Kósa D, Nemes D, et al. Self‑nanoemulsifying drug delivery systems containing Plantago lanceolata-an assessment of their antioxidant and anti‑inflammatory effects. Molecules. 2017;22(10):1773.

Han Y, Fan J, Xia W, et al. Folic acid‑functionalized PLGA nanomedicines encapsulating echinacoside for liver cancer therapy. Biochem Biophys Res Commun. 2025;774:152049.

Lee Y, Sugihara K, Gillilland MG, et al. Hyaluronic acid–bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis. Nat Mater. 2020;19(1):118‑126.

Ji C, Liu F, Huang Y, et al. Self‑assembled zinc–polyphenol–polypeptide nanocomplexes for enhanced bacterial eradication. J Polym Sci. 2025:n. pag.

Stein R, Martínez‑Navarrete M, Leão AP, et al. Curcumin and resveratrol loaded in nanostructured mesoporous silica as a promising delivery system in inflammatory bowel disease. J Drug Deliv Sci Technol. 2025;112:107262.

Khachatryan G, Khachatryan K, Krystyjan M, et al. Functional properties of composites containing silver nanoparticles embedded in hyaluronan and hyaluronan–lecithin matrix. Int J Biol Macromol. 2020;149:417‑423.

Valdés A, Artemenko KA, Bergquist J, et al. Comprehensive proteomic study of the antiproliferative activity of a polyphenol‑enriched rosemary extract on colon cancer cells using nanoliquid chromatography–orbitrap MS/MS. J Proteome Res. 2016;15(6):1971‑1985.

Chen J, Cortez‑Jugo C, Kim C, et al. Metal–phenolic‑mediated assembly of functional small molecules into nanoparticles: assembly and bioapplications. Angew Chem Int Ed Engl. 2024;63(12):e202319583.

Lu Y, Guo Y, Jin J, et al. Preparation of pH‑responsive hydrogel microspheres based on fibrillated soy protein isolate and sodium alginate and investigation of polyphenol release behavior from Ascophyllum nodosum. Food Hydrocolloids. 2026;171:111861.

Qu Y, Zhu H, Lin Z, et al. Supramolecular assembly of polyphenols and nucleic acids by thermal cycling for immune cell activation. Chem Mater. 2023;35(17):7103‑7112.

Chen Z, Farag MA, Zhong Z, et al. Multifaceted role of phyto‑derived polyphenols in nanodrug delivery systems. Adv Drug Deliv Rev. 2021;176:113870.

Wang JF. Qualitative and quantitative studies on phenylethanoid glycosides from different parts of Cistanche deserticola [dissertation]. Beijing: Peking Union Medical College; 2014. [Chinese]

Chen WJ, Wen YX, Chen YY, et al. Phenylethanoid glycosides and their cytotoxicity of Chirita eburnea Hance. Chinese Traditional Patent Medicine (Zhongchengyao). 2010;32(6):1000‑1003. [Chinese]

Yan ZL, Li B, Dai YL. Research progress in supramolecular drug delivery nanosystems based on polyphenols. Chemical Journal of Chinese Universities (Gaodeng Xuexiao Huaxue Xuebao). 2025;46(1):24‑42. [Chinese]

Zhang M, Wang L, Jin H, et al. Employing single valency polyphenol to prepare metal‑phenolic network antitumor reagents through FeOOH assistance. J Control Release. 2023;358:612‑625.

Ernest U, Chen HY, Xu MJ, et al. Anti‑cancerous potential of polyphenol‑loaded polymeric nanotherapeutics. Molecules. 2018;23(11):2787.

Zhang SL, You SP, Zhao J, et al. Protective effect of Cistanche phenylethanoid glycoside liposomes on BSA‑induced liver fibrosis in rats. Carcinogenesis, Teratogenesis & Mutagenesis (Aibian Jibian Tubian). 2019;31(6):428‑433. [Chinese]

Ma XT, Zhang SL, Wang ZQ, et al. Study on effect of liposomes from Cistanche phenylethanoid glycosides on proliferation of rrPDGF‑BB induced hepatic stellate cells and its action mechanism. Chongqing Medicine (Chongqing Yixue). 2019;48(10):1630‑1634. [Chinese]

Ma XT. Effect of CPhGs liposome on proliferation and apoptosis of HSC‑T6 and its molecular mechanisms [dissertation]. Urumqi: Xinjiang Medical University; 2019. [Chinese]

Munire K, Wang M, You SP, et al. Preparation of pPB‑modified Herba Cistanches phenylethanoid glycoside liposomes. Chinese Journal of Drug Application and Monitoring (Zhongguo Yaowu Yingyong yu Jiance). 2018;15(6):330‑333. [Chinese]

Ou ZM. Study on LRP1‑targeted echinacoside‑loaded liposomes for the treatment of Parkinson's disease [dissertation]. Beijing: China Academy of Chinese Medical Sciences; 2023. [Chinese]

Jue LL, Liang J, Li XT, et al. Preparation, in situ intestinal absorption characteristics and in vivo pharmacokinetics of echinacoside‑loaded solid lipid nanoparticles. Chinese Traditional Patent Medicine (Zhongchengyao). 2022;44(8):2429‑2434. [Chinese]

Han J, Sun Y, Wu T, et al. Echinacoside‑zinc nanomaterial inhibits skin glycation by suppressing the transcriptional activation of the receptor for advanced glycation end‑products. ACS Nano. 2023;17(14):14123‑14135.

Wang M, Ma X, Wang G, et al. Targeting UBR5 in hepatocellular carcinoma cells and precise treatment via echinacoside nanodelivery. Cell Mol Biol Lett. 2022;27(1):92.

Wu LP. Construction of acteoside lipid nanocapsules for brain‑targeted delivery of acteoside and its effects in alleviating AD [dissertation]. Hangzhou: Zhejiang University; 2023. [Chinese]

Fang DL, Chen Y, Xu B, et al. Development of lipid‑shell and polymer core nanoparticles with water‑soluble salidroside for anti‑cancer therapy. Int J Mol Sci. 2014;15(3):3373‑3388.

Zhang Y, Zhang K, Wu Z, et al. Evaluation of transdermal salidroside delivery using niosomes via in vitro cellular uptake. Int J Pharm. 2015;478(1):138‑146.

Luo M, Peng H, Deng Z, et al. Preparation and characterization of genipin‑crosslinked chitosan microspheres for the sustained release of salidroside. Int J Food Eng. 2015;11(3):323‑333.

Yu X, Sun L, Tan L, et al. Preparation and characterization of PLGA–PEG–PLGA nanoparticles containing salidroside and tamoxifen for breast cancer therapy. AAPS PharmSciTech. 2020;21(3):85.