Cerebral vascular endothelial cells constitute the structural and functional core of the BBB. In cerebrovascular events such as ischemic stroke, endothelial cell injury represents a critical early trigger for subsequent pathological cascades. Endothelial dysfunction increases BBB permeability, allowing harmful substances and inflammatory cells from the bloodstream to infiltrate the brain parenchyma, inducing cerebral edema and exacerbating neuronal damage (40). Quercetin has been shown to enhance vascular defense mechanisms through multiple synergistic pathways (44).

Beyond fortifying the vascular barrier, quercetin can also traverse the damaged BBB, albeit with limited efficiency, to exert direct effects on neurons and glial cells within the brain parenchyma, manifesting multidimensional neuroprotective effects (85).

Calcium overload has been identified as a pivotal mechanism in the pathophysiology of cerebral ischemic injury (98). Quercetin maintains intracellular calcium ion balance by upregulating expression of calcium-buffering proteins, including calbindin and parvalbumin (32). The mechanisms are as follows: first, enhanced calbindin and parvalbumin expression allows these low-molecular-weight calcium-binding proteins to absorb intracellular calcium overload, preventing excessive activation of calcium-dependent proteases such as calpain (99, 100). Additionally, quercetin reduces NMDA receptor-mediated calcium influx, exerting an indirect effect on pathological calcium influx through inhibition of glutamate excitotoxicity (101).

Regarding mitochondrial protection, quercetin stabilizes mitochondrial membrane potential, enhances electron transport chain activity, and increases ATP synthesis, thereby ensuring neuronal energy supply. This phenomenon is intimately linked to activation of the AMP-activated protein kinase signaling pathway, which plays a pivotal role in cellular energy sensing (102).

In the subacute and chronic phases of ischemic injury, angiogenesis and vascular remodeling are critical for restoring blood supply, salvaging ischemic penumbra tissue, and promoting functional recovery (103). Preliminary research indicates potential involvement of quercetin in this process. For instance, in models of peripheral ischemia, quercetin promotes endothelial cell survival, migration, and lumen formation, thereby increasing capillary density in ischemic tissue (104). However, it is crucial to acknowledge the context-dependent nature of quercetin’s role in angiogenesis, as it frequently exhibits anti-angiogenic properties in tumor studies. Consequently, further direct and in-depth investigation is required to elucidate its specific effects and molecular mechanisms on angiogenesis and remodeling in cerebral ischemia models.

In addition to the common signaling pathways it shares with other polyphenols, quercetin exhibits unique molecular interactions that are responsible for its superior protective efficacy in the cerebrovascular system. Systematic structure–activity relationship studies have shed light on the molecular basis of quercetin’s exceptional activity. An investigation into flavonoids revealed that optimal cerebrovascular protection requires (105): The 3′,4′-catechol structure in the B-ring is responsible for potent antioxidant activity and metal chelation, while the 2,3-double bond in conjugation with the 4-keto function in the C-ring enables electron delocalization. Finally, the 3-OH stabilizes the molecule and enables critical hydrogen bonding interactions with target proteins. Quercetin possesses all three of these structural prerequisites; removal or modification of any one of them substantially diminishes its activity. Comparative in vivo studies demonstrate quercetin’s superior efficacy in reducing cerebral infarct volume compared to equimolar doses of kaempferol, luteolin or catechin in MCAO models (106). These distinctive molecular properties, combined with unique metabolic bioactivation in ischemic tissue, establish quercetin as a particularly promising candidate among dietary flavonoids for cerebrovascular protection.

In summary, the neuroprotective effects of quercetin manifest as a multi-layered, multi-target network effect. This process involves fortifying vascular defenses to limit injury propagation while directly intervening in the fate of neurons and glial cells, promoting their survival and facilitating brain neuron repair. This comprehensive protective profile renders quercetin an exceptionally attractive candidate molecule for interventions in cerebrovascular diseases.

Quercetin is a prevalent constituent of many individuals’ daily diets (109). Primary sources include onions (particularly red onions), apples (especially the peel), berries (e.g., blueberries and cranberries), citrus fruits, leafy greens (e.g., mustard greens), legumes, nuts (e.g., peanuts), and black and green teas. Adopting a balanced dietary pattern rich in these foods (such as the Mediterranean diet) theoretically enables sustained quercetin intake.

Nevertheless, establishing a direct correlation between dietary quercetin intake and cerebrovascular health is encumbered by methodological challenges (110, 111). First, accurately quantifying individual quercetin intake from complex diets is extremely difficult, as it is influenced by numerous factors, including variety, ripeness, growing conditions, and storage methods (112). Particularly significant is the impact of cooking and processing methods on quercetin content and bioactivity (113). For instance, boiling may cause loss of poorly water-soluble quercetin glycosides, while high-temperature baking or frying may induce thermal degradation (114). However, specific data regarding the impact of various cooking methods on quercetin content and bioactivity in common foods remain limited in the scientific literature, creating a significant knowledge gap in evaluating the practical efficacy of dietary strategies (115).

Additionally, there is a paucity of high-quality epidemiological evidence definitively establishing a dose-dependent negative correlation between dietary quercetin intake and the risk of cerebrovascular diseases such as ischemic stroke. While research has indicated a potential correlation between flavonoid-rich dietary patterns and reduced cardiovascular disease risk, a comprehensive literature search did not yield prospective cohort studies specifically examining the relationship between quercetin monomer and cerebrovascular disease risk, particularly quantitative studies providing precise risk ratios and confidence intervals (116, 117). This evidence gap renders the establishment of a definitive daily recommended quercetin intake for cerebrovascular disease prevention challenging based on current data.

Despite administration of high-purity quercetin via supplements, its bioavailability in the human body remains significantly lower than anticipated. Its inherent poor pharmacokinetic properties constitute a core bottleneck in clinical translation, known as the “delivery gap.”

Pharmacokinetic barriers significantly impede clinical research progress. Despite extensive preclinical literature on quercetin, no large-scale, randomized, controlled Phase II or III clinical trials have been published evaluating its efficacy in treating acute ischemic stroke, secondary stroke prevention, vascular cognitive impairment, or post-stroke cognitive rehabilitation.

This “clinical research vacuum” signifies a dearth of evidence-based responses to critical inquiries: Efficacy: Can quercetin enhance neurological outcomes in stroke patients? Can it decelerate vascular cognitive impairment progression? What are the alterations in pertinent clinical endpoints, such as cognitive test scores or functional recovery scales? Dose–response relationship: What is the optimal therapeutic dose? Is there an effective dose window? Safety: What is the spectrum of adverse events in cerebrovascular disease patients during long-term or high-dose use? What is the maximum tolerated dose? Pharmacokinetic parameters: What are the specific parameters for absorption, distribution, metabolism, and excretion in patients? What are the actual drug concentrations achievable in cerebrospinal fluid or brain tissue?

Absent this high-level clinical evidence, discourse regarding quercetin’s potential as a treatment for cerebrovascular disease remains largely speculative, impeding regulatory approval and integration into clinical guidelines. Consequently, quercetin’s translational progress has stalled at a critical stage—namely, the transition from a “promising compound” to an “effective drug.”

A fundamental limitation of translating quercetin research into clinical practice is the substantial discrepancy between the concentrations that can be achieved physiologically and those that demonstrate robust protective effects in experimental systems. Following the consumption of quercetin-rich foods or standard supplements, the peak plasma concentration of total quercetin is only 0.2–2.3 μmol/L, with the free aglycone representing less than 5% of this total (121). Brain tissue concentrations are estimated to be 10–15% of plasma levels, resulting in cerebral quercetin concentrations of approximately 0.02–0.35 μmol/L in realistic dietary scenarios (122, 123). By contrast, animal studies demonstrating significant cerebrovascular protection usually employ intraperitoneal doses that produce peak plasma concentrations of 30–100 μmol/L, which is tens of times higher than the level achieved through oral administration (124).

Adding to the difficulty of putting this into practice, quercetin undergoes extensive phase II metabolism, with glucuronide, sulfate and methylated conjugates accounting for over 95% of circulating quercetin-related compounds. Comparative studies reveal that major metabolites, such as quercetin-3-O-glucuronide, have only 15–30% of the aglycone’s direct antioxidant capacity and significantly reduced NF-κB inhibitory efficacy (125). However, emerging evidence suggests that metabolites may retain activity through alternative mechanisms, including the inhibition of NADPH oxidase, and demonstrate superior BBB penetration. Subsequent intracellular deconjugation then regenerates the active aglycone (126).

These pharmacokinetic realities necessitate the cautious interpretation of preclinical data and suggest that the beneficial effects of dietary quercetin likely operate through mechanisms that are distinct from those elucidated in high-dose experimental paradigms. These mechanisms could potentially involve chronic, low-level anti-inflammatory effects, epigenetic modifications or modulation of the gut microbiome, rather than acute, pharmacological neuroprotection. Future research should prioritize physiologically relevant concentration ranges and investigate whether, despite their reduced direct potency, quercetin metabolites contribute meaningfully to cerebrovascular health through cumulative chronic exposure.

To overcome the inherent pharmacokinetic limitations of quercetin, researchers are actively exploring delivery strategies across multiple medical fields with the objective of enhancing bioavailability. These strategies include: Enzymatic modification of isoquercitrin: Polysaccharides are attached to quercetin through natural enzymatic processes (127, 128). This approach has been demonstrated to increase peak plasma concentrations by up to 40-fold, with a time to peak concentration of just 15 min (127). Furthermore, the water-soluble form of quercetin exhibits significantly stronger biological activity than original quercetin. Liposomal encapsulation: Encapsulating quercetin within spherical structures composed of phospholipids that mimic cell membranes enhances bioavailability by a factor of 50, achieving equivalent or higher plasma exposure levels at doses one-fifth of those required by conventional quercetin (129). Quercetin derivatives: Glucoside conjugates, particularly the 3-O-glucoside derived from onions, demonstrate the highest bioavailability in humans.

In the domain of nanomedicine, the utilization of nanocarriers for drug delivery is regarded as the most promising strategy to address the “delivery gap.” The fundamental principle underlying this approach entails modifying quercetin’s physicochemical characteristics and in vivo behavior through encapsulation or conjugation to nanoparticles (130). Multiple nanodelivery systems have been employed in quercetin research, substantiating their potential: (1) Liposomes and polymeric nanoparticles: As conventional nanocarriers, encapsulating hydrophobic quercetin within a lipid bilayer or polymeric core enhances water solubility and stability, protects against premature metabolic degradation, and prolongs circulation time (131). (2) Exosomes: Exosome-based nanovesicles have emerged as a promising platform for intercellular communication, exhibiting low immunogenicity and inherent trans-biological barrier capabilities. Loading quercetin into engineered vesicles holds promise for more efficient and safe targeted delivery (132, 133). Functionalization and targeted modification: To achieve precise delivery, specific targeting molecules can be modified onto nanocarrier surfaces, enabling active recognition and binding to specific receptors on brain endothelial cells or neurons (134), thereby achieving active brain targeting. For instance, a study developed a quercetin conjugate combining a mitochondrial-targeting short peptide with a CD44 receptor-targeting hyaluronic acid (135). This system exhibited triple-targeting potential, significantly enhancing neuroprotective effects. (3) Smart responsive nanoscale systems: More advanced designs involve “smart” nanocarriers, such as ROS-responsive nanoparticles engineered to respond to microenvironmental features in ischemic brain regions (e.g., elevated reactive oxygen species levels). These particles maintain stability within healthy tissues but undergo structural alterations upon reaching the lesion site, enabling on-demand drug release, thereby enhancing efficacy and reducing side effects (136). Similarly, Jian et al. (137) developed Quercetin@TPP-ROS-Lips, which are based on the anti-inflammatory and antioxidant properties of quercetin, as well as the ROS-responsive degradation characteristics of dopamine. The Quercetin@TPP-ROS-Lips were formed through the oxidatively self-assembly of dopamine to encapsulate quercetin, with rabies virus glycoprotein coated on the surface. This significantly enhanced the diffusion stability of quercetin, exhibiting ROS-responsive degradation properties. The Quercetin@TPP-ROS-Lips effectively reduced oxidative damage in SH-SY5Y cells and induced glial cell polarization toward an anti-inflammatory (M2) phenotype. Further in vivo studies demonstrated that Quercetin@TPP-ROS-Lips reduced neuronal apoptosis and significantly improved neurological deficits in a rat model of middle cerebral artery occlusion. Similarly, Zhao et al. (138) encapsulated quercetin within ROS-responsive, mitochondria-targeted liposomes to achieve at least 14 days of sustained quercetin therapy for ischemia-reperfusion injury. (4) Chemical modification: Beyond nanoparticle encapsulation, chemical modification of the quercetin molecule represents a promising avenue. For instance, glycosylation modifications enhance quercetin’s water solubility, bioavailability, and brain targeting capacity while amplifying neuroprotective effects (139).

While these advanced delivery systems have shown encouraging results in preclinical models (e.g., significantly increased intracerebral drug concentrations and more effective reduction of infarct volume), recent studies frequently lack standardized reporting of key pharmacokinetic parameters, hindering cross-study comparisons. Establishing standardized evaluation systems is imperative for selecting optimal clinical candidate formulations in the future.

Following procurement of advanced formulations capable of ensuring sufficient brain exposure, the subsequent step involves conducting rigorously designed and properly executed clinical trials. This is not only the sole pathway to validate quercetin efficacy but also an essential step in assessing patient safety. Future clinical trial designs should consider the following aspects: (1) Selecting appropriate formulations: Priority should be given to nanoformulations or chemically modified compounds that have demonstrated optimal brain targeting efficiency and safety in preclinical studies, as opposed to conventional quercetin supplements. (2) Defining target populations: Given the neuroprotective time window, quercetin formulations may be more appropriate as adjunctive therapies to existing standard treatments in acute stroke care. However, its potential for secondary stroke prevention and post-stroke cognitive rehabilitation is greater, owing to its anti-inflammatory, antioxidant, and neuroplasticity-promoting properties. Consequently, there is a compelling rationale for prioritizing long-term, multicenter randomized controlled trials focusing on these two populations. (3) Scientifically defining endpoints: Efficacy endpoints should extend beyond imaging-based infarct volume to focus on functionally meaningful patient outcomes, such as modified Rankin Scale scores, activities of daily living assessments, and standardized cognitive function scales (140, 141). (4) Strengthening pharmacokinetic and pharmacodynamic research: Concurrent pharmacokinetic and pharmacodynamic studies are imperative in clinical trials. Monitoring drug concentrations in plasma and cerebrospinal fluid, with subsequent correlation to biomarkers and clinical efficacy, will facilitate exploration of dose–response relationships and provide evidence for determining optimal dosing regimens.

Whether and how quercetin can be used to treat human cerebrovascular diseases can only be definitively answered through high-quality clinical research. This would truly achieve its transformation from a dietary component to a clinical drug.