The preparation methods of quercetin nanoparticle formulations mainly include the solvent evaporation method, ultrasonication-assisted method, self-assembly method, and spray drying method. The solvent evaporation method involves dissolving quercetin with polymers in organic solvents and then removing the solvent by evaporation to form nanoparticles. This method is simple and effective at controlling particle size (Mujtaba et al., 2019). Nonetheless, it has high demands in terms of large-scale production and solvent handling, which may have environmental impacts. The ultrasonication-assisted method utilizes the energy of ultrasound to thoroughly mix the drug and polymers, forming nanoparticles. In addition, the cavitation effect generated by ultrasound vibration, which serves to directly break down the quercetin dissolved in the organic solvent into nanoparticles in the liquid phase. This method can obtain uniform nanoparticles in a short period of time and has good adaptability for temperature-sensitive drugs (Jiang et al., 2022). The self-assembly method spontaneously forms nanostructures by changing environmental conditions such as pH and ionic strength, without the need for complex equipment and operations, although it has higher requirements for environmental conditions (Farr et al., 2018). The spray drying method involves spraying the solution of quercetin and a carrier into hot air to instantly dry and form nanoparticles. This method is suitable for large-scale production; however, it may lead to drug denaturation (Xu D. et al., 2023).

Quercetin is a naturally occurring flavonol compound characterized by a highly conjugated, rigid, and planar molecular skeleton, with the IUPAC name 3,3′,4′,5,7-pentahydroxyflavone. Its core structure consists of three ring systems: two benzene rings (Ring A and Ring B) connected via an oxygen-containing heterocyclic ring (Ring C, i.e., the pyranone ring), forming the classic C6–C3–C6 flavonoid backbone. This structure contains five phenolic hydroxyl groups (–OH) and one carbonyl group (C=O), which together serve as multiple hydrogen bond donors and acceptors. Meanwhile, the electron-rich π systems of Ring A and Ring B confer significant aromaticity and planarity, providing a structural basis for π–π stacking interactions. These structural features enable quercetin to be encapsulated by various carrier materials through multiple mechanisms. As shown in Table 1, the nanoformulations of quercetin reported in existing studies and their functional properties are presented, along with a summary of commonly used encapsulation methods.

Applying nanotechnology to deliver quercetin as nanoparticles into the bodies of arthritis patients can enhance the bioavailability and therapeutic effect of the drug. With nanocarrier technology, researchers can reduce the metabolic rate of quercetin, thereby extending the duration of its efficacy (Oliveira et al., 2022). Research shows that this technology can significantly improve the stability and solubility of quercetin, thus enhancing its effectiveness (Vinayak and Maurya, 2019). Quercetin nanomedicine also possesses targeting properties, allowing for precise release of the drug at the lesion site. Moreover, due to the EVLIS(Enhanced Vascular Leakage and Inflammatory Stimulation) effect present in RA synovium (similar to the EPR effect in tumors), quercetin nanomedicine can accumulate passively. Furthermore, high expression of folate and CD44 receptors is found at the inflammatory site, which enables the modification of active targeting ligands on the surface of the nanocarrier, thus achieving targeted delivery of the drug to the site of arthritis inflammation (Nogueira et al., 2016; Cui et al., 2024; Siddique et al., 2022). In numerous practical preclinical studies, quercetin-loaded nanofomulations have achieved significant efficacy, resulting in notable relief of arthritis symptoms and pain in model animals with rheumatoid arthritis. Therefore, quercetin-loaded nano-drugs hold great promise for application in the treatment of rheumatoid arthritis and are expected to become one of the important therapeutic options for this disease in the future.

Saleem et al. successfully prepared chitosan nanoparticles loaded with quercetin via a solvent evaporation method (Hannan et al., 2023). The hydrodynamic diameter of the nanoparticles is 83.9 nm, and the encapsulation efficiency of quercetin reaches 90.5%. In animal experiments, this nanoparticle formulation significantly alleviates joint swelling in FCA-induced RA model rats and reduces pro-inflammatory cytokine levels in plasma. Further histological examination of the joints reveals that the formulation could reduce the formation of synovial vascular hyperplasia and decrease bone damage. In addition, after treating the rats with a higher dose (20 mg/kg) of this formulation, there were no abnormalities observed in liver and kidney histology. This demonstrates that the nanoparticle formulation is virtually non-toxic and safe. In another study, Han et al. efficiently mixed Fe³⁺ with quercetin in a methanol solution to synthesize ultra-small Fe-Que nanoparticles (Han et al., 2023). These nanoparticles demonstrated excellent anti-inflammatory effects and the ability to downregulate ROS in both in vivo and in vitro experiments. Additionally, they can prevent macrophage polarization into pro-inflammatory macrophages by inhibiting the NF-κB pathway. Pharmacodynamic studies on RA model mice revealed that Fe-Que nanoparticles significantly alleviated joint swelling and inflammatory cell infiltration. Furthermore, they were able to prevent bone damage caused by bone resorption by increasing the number of anti-inflammatory macrophages in the joints (Figure 1).

Li et al. prepared microemulsions (PVGLIG-MTX-Que-Ms) through a film hydration method, with a hydrodynamic diameter of 89.6 nm (Figure 2) (Li et al., 2024). The PVGLIG in this system can be degraded by the highly expressed MMP-2 in the rheumatoid arthritis microenvironment, thus enabling the responsive release of Que at the joint site. Additionally, the surface-modified MTX can target the folate receptors on the membranes of activated macrophages. In in vitro release experiments, Que demonstrated sustained release characteristics. In cellular experiments, PVGLIG-MTX-Que-Ms exhibited low cytotoxicity and could be selectively taken up by inflammatory macrophages, significantly downregulating pro-inflammatory factors. Moreover, in the pharmacological study of CIA rats, it was found that this microemulsion could accumulate in inflamed joints, alleviating joint swelling and improving bone destruction. In drug safety evaluations, no significant toxicity of this system was observed. Table 2 summarizes the quercetin-loaded nanoformulations employed in existing rheumatoid arthritis treatment studies and their corresponding functional properties.

Osteoarthritis (OA) is a common chronic joint disease, primarily characterized by degeneration of joint cartilage, bone proliferation, and synovitis, which severely affects patients’ quality of life (Abramoff and Caldera, 2020; Molnar et al., 2021). With the increasing aging population, the incidence of OA rises annually (Peat and Thomas, 2021; Hawker and King, 2022). Current treatment methods for osteoarthritis primarily include drug therapy, physical therapy, lifestyle interventions, and surgical options. Each of these methods has its own indications, and the choice is individualized based on the patient’s specific conditions (Jang et al., 2021). Drug therapy is currently the most common choice, usually involving NSAIDs, painkillers, and supplement-type medications such as glucosamine and chondroitin (van et al., 2020). These medications aim to relieve pain, reduce inflammation, and enhance function (Kolasinski et al., 2019; Katz et al., 2021). As previously mentioned, while NSAIDs and corticosteroids can provide therapeutic benefits in the anti-inflammatory treatment of OA, they are often associated with various side effects, particularly gastrointestinal damage (Migliorini et al., 2021; Yan et al., 2021). The use of NSAIDs frequently leads to adverse reactions in the gastrointestinal tract, including peptic ulcers and gastric bleeding. Studies have shown that long-term NSAID users have a significantly increased risk of gastrointestinal damage (Weng et al., 2023). This occurs because these medications inhibit the activity of cyclooxygenase (COX) enzymes, thereby reducing the synthesis of prostaglandins, which play a crucial role in protecting the gastric mucosa and maintaining normal gastrointestinal function. When prostaglandin levels decrease, the protective mechanisms of the gastric mucosa are compromised (Sohail et al., 2023; Bindu et al., 2020; Panchal and Prince Sabina, 2023).

There are numerous literature reports that quercetin has multifaceted therapeutic effects on OA. Studies have reported that quercetin alleviates joint inflammation by inhibiting the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) (Samadi et al., 2022; Wang H. et al., 2023). Additionally, quercetin can downregulate the activity of nuclear factor kappa B (NF-κB), thereby inhibiting inflammatory signaling pathways (Zhang et al., 2020; Shao et al., 2021; Wang and He, 2022). Oxidative stress is considered an important factor in the development of OA (Ansari et al., 2020; Riegger et al., 2023; Wang W. et al., 2023). As a potent antioxidant, quercetin can scavenge free radicals in the body, reducing oxidative damage. Quercetin protects chondrocytes from the effects of oxidative stress, thereby maintaining the structure and function of cartilage (Wang et al., 2022; Xi et al., 2023). Furthermore, research suggests that quercetin can promote the proliferation and differentiation of chondrocytes while upregulating the synthesis of cartilage matrix components, such as collagen and glycosaminoglycans. This protective and promoting effect on chondrocytes helps improve joint function and slow the progression of osteoarthritis. Additionally, animal experiments and some clinical studies have shown that quercetin has a significant effect in alleviating pain and improving joint mobility by regulating the biochemical environment within the joint cavity and reducing the sensation of pain (Lv et al., 2022; Mao et al., 2024).

Although quercetin has many advantages in the treatment of OA, as previously mentioned, its transition to clinical applications hinges on improving its solubility and bioavailability through formulation techniques due to its susceptibility to oxidative metabolism and poor water solubility. Therefore, nanotechnology naturally emerges as a promising solution to address this issue. Research on nano-drugs for treating OA primarily focuses on intra-articular injection formulations of nano-gels (Mok et al., 2020; Atwal et al., 2023; Xu Y. et al., 2023). Bahtiar et al. encapsulated quercetin in lecithin-chitosan nanoparticles and then prepared it into a gel (Permatasari et al., 2019). Subsequently, the results showed that this formulation significantly downregulated pro-inflammatory factors IL-1β and MMP-9, with MMP-9 playing an important role in the degradation of cartilage tissue during the onset and progression of OA. Histological analysis of rat knee joint tissue slices confirmed that the lecithin-chitosan nano-gel loaded with quercetin could indeed alleviate inflammation and improve cartilage integrity.

Kan and his team loaded quercetin into the metal-organic framework ZIF-8 to prepare Que@ZIF-8 nanoformulations for intra-articular injections (Kan et al., 2024). In vitro experiments showed that Que@ZIF-8 nanoparticles could release pH-responsive reagents into chondrocytes, effectively protecting them from interleukin (IL)-induced inflammation and apoptosis, thus promoting cartilage synthesis activity. The results suggested that the potential mechanism revealed a significant increase in autophagy in IL-β-treated chondrocytes, subsequently inhibiting the Pi3k/Akt signaling pathway, which plays a promoting role in the protective effect of Que@ZIF-8. In therapeutic experiments on unstable meniscal osteoarthritis (OA) mice, Que@ZIF-8 significantly improved the structural integrity of cartilage and chondrocyte status and slowed down the progression of OA. Importantly, due to its controlled release, Que@ZIF-8 demonstrated superiority over quercetin alone in the treatment of OA.