Edge advances in nanodrug therapies for osteoarthritis treatment

Abstract

As global population and lifestyles change, osteoarthritis (OA) is becoming a major healthcare challenge world. OA, a chronic condition characterized by inflammatory and degeneration, often present with joint pain and can lead to irreversible disability. While there is currently no cure for OA, it is commonly managed using nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and glucosamine. Although these treatments can alleviate symptoms, it is difficult to effectively deliver and sustain therapeutic agents within joints. The emergence of nanotechnology, particularly in form of smart nanomedicine, has introduced innovative therapeutic approaches for OA treatment. Nanotherapeutic strategies offer promising advantages, including more precise targeting of affected areas, prolonged therapeutic effects, enhanced bioavailability, and reduced systemic toxicity compared to traditional treatments. While nanoparticles show potential as a viable delivery system for OA therapies based on encouraging lab-based and clinical trials results, there remails a considerable gap between current research and clinical application. This review highlights recent advances in nanotherapy for OA and explore future pathways to refine and optimize OA treatments strategies.

1 Introduction

Osteoarthritis (OA) is a prevalent condition, affecting over 500 million people worldwide, which is equates to approximately 7% of the world’s population (Duan et al., 2023). From 1990 to 2019, the prevalence of OA increased by 48% (Hunter et al., 2020), underscoring its growing impact. Research increasingly indicates that factors such as obesity, aging, poor dietary habits, and hypertension significantly contribute to the progression of OA (Colletti and Cicero, 2021). The primary objectives in managing OA are pain relief, reduce of joint inflammation, enhancing joint function, and minimizing overall disability (Filardo et al., 2015; De Faro Silva et al., 2022). Standard treatment typically involves intra-articular drug injections and surgical interventions (Ebert et al., 2013); however, these approaches often fall short in efficacy. Surgical treatments, in particular, are complex and require prolonged recovery periods (Conaghan et al., 2019). While commonly used clinical treatments like NSAIDs, glucocorticoids, and glycosaminoglycan can provide symptomatic relief, but do little to halt the progression of OA (Katz et al., 2021), highlighting the urgent need for more effective treatments.

In recent decades, significant progress has been made in the field of nanomedicine for treating various diseases (Janowicz et al., 2022; Zhang Z. et al., 2022; Han and Huang, 2023). In the context of OA, researchers are working on developing nanocarrier systems to utilize nanoparticles to extend the duration of drug efficacy, allowing for a gradual release of the therapeutic agents and improving their penetration into chondrocytes or synovial cells (Mitchell et al., 2021; Dilliard et al., 2021; Boehnke et al., 2022). Despite these promising advancements, no nanotherapeutic drugs for OA have yet received clinical approval. This review aims to explore recent developments in nanomedicine for OA treatment, providing a comprehensive overview of its properties, potential benefits, and the challenges that must be addressed for clinical application.

2 Pathogenesis of osteoarthritis

Osteoarthritis (OA) is characterized by a complex interplay of pathological changes within affected joints, including the deterioration of articular cartilage (Krishnan and Grodzinsky, 2018), inflammation of the synovial membrane (Hu et al., 2019), remodeling of the subchondral bone (Zhu et al., 2021), and the development of osteophytes (McCulloch et al., 2017). The widely accepted theory is that OA arises from an imbalance between degradation and repair of cartilage (Guilak et al., 2018). Articular cartilage, which is crucial for smooth joint movement, consists primarily of chondrocytes embedded in an extracellular matrix (ECM) rich in type II collagen and proteoglycans (Zou et al., 2021). Under normal conditions, chondrocytes maintain cartilage integrity by synthesizing type II collagen and proteoglycans while also regulating the activity of enzymes such as matrix metalloproteinases (MMPs). These enzymes are responsible for maintaining a balance between the breakdown (catabolism) and synthesis (anabolism) of cartilage components (Guo et al., 2018; Li T. et al., 2022).

Various factors, including mechanical stress, metabolic changes, aging, and inflammation, contribute to the progression of OA. Mechanical stress, such as that caused by joint overuse or injury, can lead to the release of damage-associated molecular patterns (DAMPs) from damaged tissues, which activate pattern recognition receptors (PRRs) on immune cells line macrophages (Li and Wu, 2021). This, in turn, stimulates the production of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1β (IL-1β) (Molnar et al., 2021). Obesity exacerbates this process through chronic low-grade inflammation, known as “metaflammation”, where expanded adipose tissue expansion leads to increased macrophage infiltration pro-inflammatory M1 phenotype, characterized by high levels of TNF-α and IL-1β production (Li et al., 2023). Aging further contributes to OA through “inflammaging,” a state of chronic, low-grade inflammation driven by the accumulation of senescent cells, oxidative stress, and altered immune function, all of which contribute to increased production of inflammatory (Chow and Chin, 2020; Wojdasiewicz et al., 2014; Liu et al., 2022a).

Inflammatory cytokines have a profound effect on chondrocytes, leading to phenotypic changes that disrupt cartilage homeostasis. These cytokines suppress the production of type II collagen and proteoglycans in chondrocytes by activating pathways like Mitogen-Activated Protein Kinase (MAPK) and Nuclear Factor-kappa B (NF-κB), particularly through the influence of mediator like prostaglandin E2 (PGE-2), Nitric Oxide (NO), and cyclooxygenase-2 (COX-2) (Ma et al., 2016; Teng et al., 2023; Chen et al., 2018; Yao et al., 2022; Lu R. et al., 2023). This shift increases the production of specific MMPs (e.g., MMP1, MMP3, MMP9, MMP13) while reducing the synthesis of collagen and proteoglycans (Ling et al., 2021; Tian et al., 2021), which collectively contribute to the breakdown of the ECM.

As ECM breaks down, it releases various molecular fragments that act as DAMPs, further activating PRRs on macrophages and chondrocytes (Son et al., 2020; Lambert et al., 2021; Foell et al., 2007; Rahmati et al., 2016; Hügle et al., 2022). This perpetuates the inflammatory cycle, enhancing the activation of NF-κB and MAPK pathways, and accelerating cartilage degradation (Moon et al., 2018; Liao et al., 2020; Xu et al., 2022; Boehme and Rolauffs, 2018). Additionally, hypoxia within the joint microenvironment exacerbates inflammation, activating the NLRP3 inflammasome in macrophages and leading to the release of pro-inflammatory cytokines such as IL-8, MCP-1, CXCL12, CCL22, and MIP-1α (Quero et al., 2020; Raghu et al., 2017; Kuang et al., 2020; Ren et al., 2021; Hou et al., 2020; Zhao et al., 2020). These cytokines contribute to the recruitment and activation of additional immune cells, further perpetuating the inflammatory cycle (Nelson et al., 2011) (Figure 1).

FIGURE 1

As OA progresses, cartilage degeneration extends into the calcified layer, promoting pathological changes in the subchondral bone, including the formation of osteophytes around the joint periphery (Hu et al., 2021; Roelofs et al., 2020). Addressing these inflammatory pathways and restoring the balance between cartilage degradation and synthesis are critical strategies in preventing and treating OA.

3 Nanomedicines to reduce inflammation of synovial and articular cartilage

Current clinical approaches to OA treatment are categorized into three main types: non-pharmacologic management, pharmacologic management, and surgical interventions (Emami et al., 2018; Evans et al., 2014). Non-pharmacologic methods, such as exercise and physical therapy, are often employed to alleviate symptoms. However, there strategies primarily address the symptoms rather than the underlying pathology of OA, and in some cases, improper application may exacerbate the condition (Lin et al., 2023; Furtado et al., 2022). Surgical interventions, such as arthroscopic surgery or joint replacement, provide more direct solution but are associated with high costs, invasiveness, and substantial risks, particularly in elderly patients or those with comorbidities (Skou et al., 2015).

Pharmacologic treatments, although less invasive than surgery, also present significant limitations. Commonly used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), glycosaminoglycans (GAGs), opioid analgesics, steroids, and hyaluronic acid (HA), can be administered via various routes, including oral, intravenous, intra-articular, and transdermal methods (McGuckin et al., 2022; Oo et al., 2021). Despite their widespread use, these pharmacologic approaches are hindered by issues such as limited local drug concentration in the joints, rapid drug clearance from synovial fluid, and systemic side effects, including gastrointestinal, renal, and cardiovascular complications, particularly with long-term use (Evans et al., 2014; Togo et al., 2022; Cooper et al., 2019).

Nanotechnology has emerged as a promising avenue for overcoming the limitations of traditional OA therapies. Nanoparticles, when utilized as drug carriers, have the unique ability to selectively accumulate in affected joints, minimizing systemic exposure and maximizing local therapeutic effects (Huang et al., 2022; Li X. et al., 2021). These carriers can also stabilize encapsulated drugs, enabling controlled and sustained release, which prolongs drug retention time and reduces site-specific toxicity (Huang et al., 2022). Moreover, nanomaterials can be engineered as stimulus–responsive drug delivery systems, triggered by external stimuli such as temperature, magnetic fields, and electric fields (Said et al., 2019). This targeted and on-demand drug delivery system enhances therapeutic efficacy while mitigating the risk of side effects.

Nanomedicine in OA treatment involves the delivery of various therapeutic agents, including small-molecule drugs, nucleic acids, and peptides/proteins, via nanomaterials designed to inhibit OA progression. By offering more precise, sustained, and responsive drug delivery, nanomedicine holds significant promise for improving OA management, addressing both symptoms and underlying pathologies, and overcoming the limitations of traditional therapies (Dou et al., 2020; Kumar et al., 2019; Xu et al., 2023).

3.1 Combination of nanotechnology with anti-inflammatory drugs

OA is a multifactorial disease characterized by the progressive degradation of joint cartilage and the inflammation of synovial membranes (Scanzello and Goldring, 2012). Inflammation is a key driver of OA progression, where inflammatory cytokines, such as TNF-α and IL-1β, play a central role. Traditional pharmacological interventions like NSAIDs, glucocorticoids (GCs), steroids, and Glycosaminoglycans (GAGs), aim to alleviate symptoms by suppressing inflammation (Strokotova and Grigorieva, 2022; Magni et al., 2021; Nunes et al., 2021). However, these treatments often have limited efficacy and are associated with significant systemic side effects. The development of nanomedicines offers a promising alternative. Some nanoparticles are designed to target the inflamed synovium and cartilage directly. By encapsulating anti-inflammatory agents within these nanovesicles, these nanomedicines can achieve sustained drug release and higher local drug concentrations within the joints (Wang Y. et al., 2022; Wen et al., 2023). This targeted approach not only enhances the therapeutic potential of existing drugs, but also minimized the adverse effects. Another strategy explored the use of metallic nanoparticles. Some metallic particles can directly act on biological molecules, they can either act as nanoenzyme to reduce oxidative stress, or act through inhibition of the NF-κB signaling pathway or activation of NLRP3 inflammasome (Li R. et al., 2022; Luo et al., 2021; Ma, 2023) (Figure 2). In the following sections, we will explore the application of nanomedicines for reducing inflammation in OA, focusing on the mechanisms by which these advanced therapies can improve clinical outcomes by targeting the synovial and articular cartilage.

FIGURE 2

3.1.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs such as ibuprofen, flurbiprofen, diclofenac, celecoxib, indomethacin, meloxicam, piroxicam, and naproxen, are among the most widely prescribed medications for alleviating symptoms in OA patients. Their primary mode of action involves robust inhibition of cyclooxygenase (COX) enzymes, particularly COX-1 and COX-2 at sites of inflammation, which in turn suppresses the biosynthesis of prostaglandins (PGs) (Ahmadi et al., 2022; Eisenstein et al., 2022; Stiller and Hjemdahl, 2022; Busa et al., 2022). PGs play a key role in sensitizing pain pathways by interacting with TRPV1, Nav1.8 and other ion channels to reduce their threshold, leading to heightened pain perception, amplifying pain perception (Magni et al., 2021; Zhu et al., 2020).

Besides their primary COX-inhibitory action, NSAIDs also modulate various other inflammatory pathways in OA, they reduce the production of pro-inflammatory cytokines and leukotrienes, which are central to joint inflammation and tissue degradation (Alvarez-Soria et al., 2006; Maślanka and Jaroszewski, 2013; Hassan and Ghobara, 2016; Li et al., 2018; Nagy et al., 2017). Furthermore, NSAIDs exert immunomodulatory effects by inhibiting the activation and migration of immune cells (Molnar et al., 2021; Li Z. et al., 2021). This broad spectrum, of anti-inflammatory actions make NSAIDs effective in managing the symptoms of OA. However, long-term use of NSAIDs is associated with several adverse effects, including gastrointestinal (GI) distress, peptic and duodenal ulcers, small bowl erosion, colitis, acute renal failure, hypertension, chronic kidney disease, heart failure, myocardial infarction, stroke, seizures, and delayed wound healing (Sohail et al., 2023; Chevalier et al., 2009). These risks have driven research towards improving NSAID delivery methods to enhance their therapeutic index while minimizing systemic side effects.

Nanotechnology has significantly advanced the field of drug delivery, offering innovative solutions to overcome the limitation associated with traditional drug delivery. Encapsulating NSAIDs within nanoscale carriers, provides several advantages, including protection from premature degradation, targeted drug delivery, and controlled release (Ashfaq et al., 2023). These nanocarriers typically range from 10–200 nm in size, typical nanocarriers that are used to encapsulating NSAIDs are liposomes, polymeric nanoparticles, and solid lipid nanoparticles (SLNs) (Badri et al., 2016; Pontes et al., 2022).

Liposomes are composed of lipid bilayers, which can encapsulate both hydrophilic and hydrophobic NSAIDs (Lee, 2020). Liposomes can be engineered to release the drug in response to specific stimuli, such as changes in pH or temperature, making them effective for localized delivery in inflamed joints (Liu P. et al., 2022). This stimulus-responsive release mechanism is particular effective for localized drug delivery with inflamed joints thereby reducing systemic exposure and associated side effects.

Polymeric nanoparticles are made from biocompatible and biodegradable polymers, these nanoparticles can encapsulate NSAIDs, ensuring a sustained release over time (Baek et al., 2017). This controlled release minimizes the need for frequent dosing and reduces systemic side effects.

SLNs are composed of solid lipids, which remain solid at body temperature. The surface of SLNs can be further coated with enteric polymers that are resistant to acidic environments, by using the combination of solid lipids and enteric coatings, SLNs are designed to bypass the stomach without releasing their contents (Pandey et al., 2021). The SLNs then release the NSAID once they reach the more neutral pH of the intestines or are absorbed into the bloodstream (Mancini et al., 2021). Once the SLNs reach the joint environment, their stability is influenced by the specific modifications made to the nanoparticle (Hsu et al., 2023). For example, SLNs can be designed to degrade in response to enzymes that are overexpressed in the inflamed joint, such as matrix metalloproteinases (MMPs). When these enzymes come into contact with the SLNs, they break down the solid lipid matrix, releasing the encapsulated NSAID directly into the inflamed tissue (Chuang et al., 2018). This coating dissolves only in the more neutral pH of the small intestine, allowing the SLNs to remain intact until they are absorbed into the bloodstream. SLNs offer a stable platform for NSAID delivery, with enhanced bioavailability and reduced gastrointestinal side effects due to localized drug release (Singh et al., 2019).

In comparison to SLNs or liposomes, inorganic nanoparticles, such as silica (SiO₂), gold (AuNPs), iron oxide (Fe₂O₃ or Fe₃O₄), or cerium oxide (CeO₂), provide a unique advantage in delivering NSAIDs for OA treatment because of their structural robustness, precise targeting capabilities, and high stability in various physiological environments (Corsi et al., 2023; Pourmadadi et al., 2022; He et al., 2021; Kalashnikova et al., 2020). Inorganic nanoparticles are inherently stable under a wide range of pH conditions, including the acidic environment of the stomach, making them highly effective for drug delivery, including NSAID encapsulation. Their robust structure prevents the encapsulated NSAID from being exposed to gastric acid, thereby protecting it from premature degradation (Hsu et al., 2023). The surface of inorganic nanoparticles can be modified with targeting ligands, such as antibodies, peptides, or small molecules that recognize and bind to specific receptors overexpressed in inflamed joints. For example,: folate receptors, which are often overexpressed in inflamed tissues, can be targeted by modifying the surface of inorganic nanoparticles with folate molecules. This targeting mechanism can lead to increased drug accumulation in the inflamed joint, improving therapeutic efficacy while reducing systemic side effects (Yu et al., 2010; Sanità et al., 2020; Huang et al., 2024). In the context of OA treatment, inorganic nanoparticles can enhance the bioavailability and therapeutic action of NSAIDs by providing protection against premature degradation, enabling controlled release, and improving tissue targeting (Yi et al., 2024).

3.1.2 Glycosaminoglycans (GAGs)

Glycosaminoglycans (GAGs), such as hyaluronic acid (HA), chondroitin sulfate, and keratan sulfate, are essential components of the extracellular matrix in cartilage. They help maintain the structural integrity and mechanical function of cartilage by providing lubrication and shock absorption in joints. HA is the most commonly used GAG in the treatment of OA (Altman et al., 2015; Testa et al., 2021; Jargin, 2012). HA products vary in molecular weight and cross-linking, which influences their viscosity and duration of action within the joint. These formulations are either derived from bacterial fermentation or extracted from rooster combs and must undergo purification to remove impurities (Serra et al., 2023).

HA is administered via intra-articular injection to restore the viscoelastic properties of synovial fluid, reducing pain and improving joint mobility (Legré-Boyer, 2015; Chavda et al., 2022). Beyond its lubricating function, HA also modulates the inflammatory response by inhibiting the activity of pro-inflammatory cytokines and enzymes, such as matrix metalloproteinases (MMPs), which degrade cartilage (Marinho et al., 2021). Furthermore, HA can inhibit the activation of the NF-κB pathway, thereby reducing the expression of inflammatory mediators like COX-2 and MMPs (Marinho et al., 2021). It may also influence the MAPK signaling pathway, affecting cell survival and inflammation (Chen et al., 2019).

Since HA is typically applied directly into the affected joint, nanoparticle technologies for HA-based treatments aim to overcome different challenges than those associated with NSAIDs. While NSAIDs nanoparticles formulations target tissue-specific delivery to inflamed joints, HA-based treatments focus on extending the therapeutic effects, enhancing stability, and improving cartilage penetration. One key limitation of HA is its rapid degradation due to enzymatic activity and its large molecular size, which restricts penetration into deeper cartilage layers (Gan et al., 2024). To address these issues, various nanoparticle technologies have been explored. For instance, poly (lactic-co-glycolic acid) (PLGA) nanoparticles can encapsulate HA, protecting it from enzymatic degradation and enabling sustained release over time. Additionally, PLGA nanoparticles can also be modified with polyethylene glycol (PEG) to increase circulation time and reduce immune clearance (Pontes et al., 2022; Zerrillo et al., 2022; Householder et al., 2023). Natural polymers such as chitosan, alginate, and cellulose derivatives show therapeutic potential for intra-articular drug delivery. Chitosan is another promising natural polymer for nanoparticle formation with HA. Its mucoadhesive properties help retain the nanoparticles in the joint, and its positive charge facilitates interaction with the negatively charged cartilage, improving penetration (Pontes et al., 2022). Other nanoparticle systems, such as hollow mesoporous silica nanoparticles (HMSNs) and liposomes can also be used to encapsulate HA. HMSNs offer a porous surface for control release, while liposomes protect HA from enzymatic degradation and allow for sustained delivery (Wen et al., 2023; Teixeira et al., 2022).

Overall, the application of nanoparticle technologies in HA-based OA treatments focuses on prolonging the therapeutic effects of HA, enhancing its stability, and improving its penetration into cartilage tissue, rather than focusing on tissue-specific delivery as is the case with NSAIDs.

3.1.3 Natural products from medicinal plants

Natural plant-derived medicines have gained significant attention in the treatment of OA due to their potential to offer anti-inflammatory, analgesic, and cartilage-protective effects with fewer side effects compared to conventional pharmaceuticals (Fang et al., 2024; Akhileshwar Jha et al., 2024; Mu et al., 2022). The significance of plant-based therapies in OA treatment is seen from multiple perspectives, including their historical use in traditional medicine, increasing scientific validation, and the growing interest in integrative approaches to managing chronic diseases like OA (Kuang et al., 2023). However, many plant-derived compounds face challenges such as poor bioavailability, rapid metabolism, and insufficient tissue targeting. Nanoparticle technologies present a promising solution by enhancing the delivery, bioavailability, and therapeutic efficacy of these compounds, improving their potential in OA treatment. While clinical studies on nanoparticles for OA are still in early stages, preclinical data suggest that multiple natural products-loaded nanoparticles could represent a novel and effective approach for mitigating OA symptoms and slowing disease progression (Fang et al., 2024; Cao et al., 2022).

Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has been recognized for its anti-inflammatory and analgesic properties (Lowin et al., 2020). It interacts primarily with the endocannabinoid system (ECS), specifically CB1 and CB2 receptors, which play roles in modulating pain, inflammation, and immune responses (Fine and Rosenfeld, 2013; Vučković et al., 2018). CBD reduces pro-inflammatory cytokine production, inhibits immune cell, and mitigates oxidative stress, all contributing to joint protection in OA. However, due to its lipophilic nature and poor bioavailability, traditional oral administration of CBD can be inefficient (Bryk and Starowicz, 2021). Nanotechnology can enhance CBD’s delivery by encapsulating it in lipid-based nanoparticles similar as encapsulating NSAIDs. Liposomes, polymeric nanoparticles, or SLNs, have been employed to improve CBD’s solubility, bioavailability, and stability (Assadpour et al., 2023; Alcantara et al., 2024). Nanoparticles, especially those functionalized with targeting ligands, can direct CBD to inflamed joints, thereby enhancing its therapeutic potential while minimizing systemic side effects. For instance, CBD-loaded PLGA nanoparticles have been shown to enhance bioavailability, allowing for more effective delivery to target tissues, by reducing inflammation and improving the therapeutic outcomes associated with OA (Jin et al., 2023).

3.1.3.1 Curcumin (Curcuma domestica)

Curcumin, a polyphenol derived from turmeric (Curcuma longa), is well-recognized for its anti-inflammatory properties (Salehi et al., 2019), particularly its ability to inhibit the NF-κB pathway, which is central to inflammation in OA (Buhrmann et al., 2021). Additionally, curcumin scavenges free radicals, reducing oxidative stress in affected joints. However, curcumin’s low solubility in water and rapid metabolism limits its clinical use (Crivelli et al., 2019; Guan et al., 2022). SLNs can enhance the oral bioavailability of curcumin by protecting it from the acidic environment of the stomach and enabling sustained release (Ban et al., 2020). It is also reported that the curcumin can be dissolved with mPEG (5kD)-PCL(2kD) polymer to produce the curcumin-loaded polymeric micelles, which has a 74.8 ± 8.68 days nm (Gupta et al., 2020; Kang et al., 2020). This approach can improve curcumin’s solubility and enhance its systemic circulation time, allowing for more effective delivery to the joints (Kang et al., 2020).

3.1.3.2 Boswellia serrata (boswellic acid)

Boswellic acid, from Boswellia serrata (Indian frankincense), inhibits the 5-lipoxygenase enzyme, reducing leukotriene synthesis, which is involved in inflammation and pain (Börner et al., 2021; Gomaa et al., 2021). It also protects cartilage by reducing the degradation caused by MMPs (Shin et al., 2022). Due to its hydrophobic nature and poor gastrointestinal absorption, nanoparticle systems such as nanoemulsion and cyclodextrin inclusion complex have been developed to improve the bioavailability of boswellic acid (Ting et al., 2018). Different from nanocapsules where the drug is confined to a cavity surrounded by a polymeric membrane and are typically 10–500 nm in size, nanoemulsions are colloidal dispersions where two immiscible liquids, typically oil and water, are stabilized by surfactants. The droplets in nanoemulsions are usually in the range of 20–200 nm, with the drug is dissolved in the dispersed phase (Borrajo et al., 2024). Instead of protecting the drug from the harsh acidic environment of the stomach and the enzymatic activity in the intestine, nanoemulsions are designed to enhance the digestion of encapsulated lipophilic compounds by allowing them to be more easily absorbed through the intestinal lining. They can enhance solubility and bioactivity of boswellic acids in the gastrointestinal tract (Choi and McClements, 2020; Han et al., 2022). The small droplet size and large surface area of nanoemulsions enable better absorption and distribution of the boswellic acids, enhancing their therapeutic effects. Cyclodextrins improve the solubility and stability of hydrophobic drugs by forming inclusion complexes where the drug is hosted inside the hydrophobic cavity of the cyclodextrin molecule. Cyclodextrin complexes can help the boswellic acids dissolve more easily in the aqueous environment of the GI tract, improving its bioavailability (Sarabia-Vallejo et al., 2023). Similarly, cyclodextrin complexations do not protect boswellic acids from the acidic environment like nanocapsules but rather enhance the drug’s solubility and absorption in the intestines (Tambe et al., 2018).

3.1.3.3 Quercetin

Quercetin, a flavonoid found in various fruits and vegetables, exhibits anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines and oxidative stress, as well as stabilization lysosomal membranes and protecting chondrocytes (Aldrich et al., 2023). Quercetin’s protective role in cartilage involves inhibiting MMPs and promoting autophagy, which helps maintain cartilage healthy (Li W. et al., 2021; Wang L. et al., 2022). However, like many natural compounds, quercetin has low bioavailability due to poor absorption and rapid metabolism (Carrillo-Martinez et al., 2024). Nanoparticle approaches, including quercetin-loaded liposomes, polymeric nanoparticles, solid lipid nanoparticles (SLNs), as while as nanostructured lipid carriers (NLCs) that are lipid-based delivery systems that combine both solid and liquid lipid, have been developed to enhance quercetin’s bioavailability, stability, and targeted delivery to inflamed joints, making it a more viable treatment option for OA (Carrillo-Martinez et al., 2024). Quercetin-loaded nanoparticles, when administered intra-articularly, showed prolonged retention in joint tissues, providing sustained release of quercetin and improving its anti-inflammatory effects in OA models (Akhileshwar Jha et al., 2024; Jennings et al., 2016). Besides the lipid nanoparticles, gold nanoparticles have been explored as carriers for various bioactive compounds, including quercetin. Due to their small size, AuNPs can efficiently deliver quercetin to targeted sites, enhancing cellular uptake and therapeutic efficacy (Sadalage et al., 2021).

3.1.3.4 Baicalin (Scutellaria baicalensis)

Baicalin, a flavonoid derived from Scutellaria baicalensis, is known for its potent anti-inflammatory, antioxidant, and chondroprotective effects, making it an attractive candidate for the treatment of OA (Hu et al., 2022). However, like many other natural compounds, baicalin suffers from poor water solubility, low bioavailability, and rapid systemic clearance, which limit its therapeutic potential in clinical applications (Huang et al., 2019). To address these limitations, various nanoparticle-based delivery systems have emerged as a promising strategy to enhance effectiveness of baicalin in OA management.

Lipid-based nanoparticles, including liposome, SLNs and NLCs, have been explored for improving baicalin’s bioavailability and targeted delivery to inflamed joints (Zhang et al., 2016; Shi et al., 2016). There nanoparticles protect baicalin from rapid degradation, facilitate sustained release, and improve its solubility in biological fluids. For instance, baicalin-loaded SLNs have demonstrated enhanced anti-inflammatory activity and greater cartilage protection in OA models, compared to baicalin in its free form (Gao et al., 2022). Another innovative approach involves the use of polymeric nanoparticles, particularly those made from biodegradable materials like PLGA. These nanoparticles allow for the controlled release of Baicalin, ensuring prolonged therapeutic effects at the site of inflammation. Functionalization of these nanoparticles with targeting ligands, such as hyaluronic acid, further enhances their ability to accumulate in osteoarthritic joints by targeting CD44 receptors expressed on synovial cells, which are implicated in OA pathology (Gaio et al., 2020; Salathia et al., 2023; Bigaj-Józefowska and Grześkowiak, 2022).

Nanoparticles provide sustained release and enhanced targeting of inflamed tissues. Additionally, lipid-based nanoparticles, such as SLNs and nanoemulsions, can further improve baicilin’s solubility and systemic circulation, allowing for more efficient delivery to OA-affected joints (Ashfaq et al., 2023; Ghasemiyeh and Mohammadi-Samani, 2018). Moreover, nanofibers and hydrogels have been employed as localized delivery platforms for baicalin (Wang Z.-Z. et al., 2022; Liu et al., 2022c). These nanostructures can be injected directly into the joint space, providing a sustained release of baicalin over an extended period. This localized administration minimizes systemic side effects while maintaining high concentrations of the active compound in the affected joints (Bai et al., 2021).

3.1.3.5 Andrographolide (AG)

Andrographolide (AG), extracted from Andrographis panicula, is a potent anti-inflammatory compound known for its ability to modulate immune responses and inhibit pro-inflammatory cytokine production (Xiong et al., 2021). Its application in OA treatment, however, is limited due to poor water solubility and rapid systemic clearance (Zhao et al., 2019). Recent advancements in nanotechnology have enabled the development of AG-loaded nanoparticles that can overcome these limitations. For instance, AG encapsulated in poly (acrylic acid)-modified mesoporous silica nanoparticles has been shown to provide a pH-responsive platform for sustained release, allowing the drug to be released more effectively in the acidic environments of inflamed OA joints (He et al., 2021). This targeted delivery not only improves AG’s therapeutic efficacy but also minimizes systemic side effects (Cheng et al., 2023). Another innovative approach involves the use of AG-loaded liposomes, which enhance the stability and bioavailability of AG, while allowing for controlled release in the affected joint tissues, thereby reducing inflammation and protecting cartilage from degradation. Although clinical applications of AG nanoparticles in OA remain in their early stages, preclinical studies suggest promising therapeutic outcomes (He et al., 2021; Hodgkinson et al., 2022).

3.1.3.6 Diacerein (DIA)

Diacerein (DIA) is a widely studied anti-inflammatory drug used to slow the progression of OA (Bernetti et al., 2019). It inhibits the synthesis of pro-inflammatory cytokines like IL-1β, reducing cartilage degradation. However, DIA is associated with gastrointestinal side effects, which limit its long-term use (Panova and Jones, 2015). Nanoparticle-based delivery systems, such as PLGA nanoparticles, have been employed to enhance the bioavailability and minimize the adverse effects of DIA (Jung et al., 2020). DIA-loaded PLGA nanoparticles provide a sustained release profile, ensuring that therapeutic levels of the drug are maintained for extended periods within the joint space. This not only reduces the frequency of administration but also improves patient compliance (Jung et al., 2020). Another advanced approach involves the development of pH-responsive DIA-loaded nanoparticles, which allow for drug release specifically in inflamed environments, minimizing side effects while maximizing efficacy in OA treatment. Although human clinical trials are still ongoing, these innovations represent a significant step forward in enhancing the therapeutic utility of DIA for OA (Hu et al., 2020).

3.1.3.7 Naringin nanoparticles

Naringin, a flavonoid derived from citrus fruits, has gained attention for its ability to promote cartilage regeneration and inhibit inflammatory pathways, making it a valuable candidate for OA therapy (Gan et al., 2023; Peng et al., 2024). However, like many other natural compounds, its clinical use is hindered by poor bioavailability and rapid clearance. Nanotechnology has provided solutions to these challenges through the development of advanced delivery systems. For example, polycaprolactone/polyethylene glycol-naringin (PCL/PEG-Nar) nanofiber membranes have been developed as a pH-responsive system for the sustained release of Naringin in OA-affected joints (Lan et al., 2020). This innovative approach ensures a steady release of the compound over time, reducing the severity of OA symptoms and promoting cartilage repair. Another promising technique involves the use of Naringin-loaded SLNs, which enhance the compound’s stability, bioavailability, and controlled release within joint tissues. SLNs have the added advantage of being biocompatible and biodegradable, making them an ideal platform for long-term OA treatment (Munir et al., 2021). While clinical applications of Naringin nanoparticles are still under investigation, preclinical studies have shown promising results, particularly in reducing inflammation and promoting cartilage regeneration in OA models (Ravetti et al., 2023).

3.2 Metallic nanoparticles in the treatment of OA

Oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidant defenses, plays a crucial role in the pathophysiology of OA. Excessive ROS disrupts redox signaling and damages key macromolecules such as proteins, lipids, and DNA, accelerating cartilage degradation and exacerbating joint inflammation (Ansari et al., 2020). In additionally, OA is also characterized by the activation of pro-inflammatory pathways, notably the NF-κB pathway, and the NLRP3 inflammasome, both of which contribute to the production of pro-inflammatory cytokines and enzymes responsible for cartilage breakdown (Ramirez-Perez et al., 2022; Xiao and Zhang, 2023; Yang et al., 2022).

Recent advances in nanotechnology have highlighted metallic nanoparticles (MNPs) as potential therapeutic agents for OA, not only as carriers for drugs and natural compounds but also as a promising therapeutic approach to directly counteract these destructive processes (Akhileshwar Jha et al., 2024). Metallic nanoparticles such as gold (AuNPs), silver (AgNPs), cerium oxide (CeO₂NPs), and zinc oxide (ZnONPs) have shown potent antioxidant properties by scavenging ROS and reducing oxidative damage. Furthermore, these nanoparticles can directly modulate inflammatory processes and inhibit cartilage degradation, targeting key pathways like NF-κB and NLRP3 inflammasome activation, thus offering new possibility for OA treatment (Nayal et al., 2024).

3.2.1 Gold nanoparticles

Gold nanoparticles (AuNPs) are extensively studied for their anti-inflammatory and antioxidative effects. AuNPs counteract oxidative stress, a major driver of OA, by scavenging ROS and restoring redox balance. Their inhibition of the NF-κB pathway reduces the production of pro-inflammatory cytokines like IL-1β and TNF-α, thus mitigating cartilage degradation and synovial inflammation (Wen et al., 2023; Abdel-Aziz et al., 2021). Functionalized AuNPs can neutralize ROS through interaction with protein thiol groups, further preventing cartilage damage. AuNPs also have favorable biocompatibility and low toxicity, though their tendency to accumulate raises concerns about long-term safety. Moreover, the high cost of gold limits large-scale production (Kus-Liśkiewicz et al., 2021).

3.2.2 Silver nanoparticles

Silver nanoparticles (AgNPs) exhibit strong anti-inflammatory and antimicrobial properties, offering dual protection by reducing inflammation and preventing infections that may exacerbate OA (Ferdous and Nemmar, 2020; Gherasim et al., 2020). AgNPs effectively scavenge ROS and inhibit the NF-κB pathway, thereby lowering the production of matrix metalloproteinases (MMPs) and other cartilage-degrading enzymes (He et al., 2024; Akter et al., 2018). Furthermore, AgNPs can be incorporated into hydrogels or nanocomposites to provide sustained anti-inflammatory effects. However, their relatively higher cytotoxicity poses limitations for long-term use (Pangli et al., 2021; Nandhini et al., 2024).

3.2.3 Cerium oxide nanoparticles

Cerium oxide nanoparticles (CeO₂NPs), or nanoceria, stand out due to their redox-active properties, mimicking natural antioxidant enzymes like superoxide dismutase (SOD) and catalase (Dhall and Self, 2018). These nanoparticles continuously scavenge ROS through their ability to switch between Ce³⁺ and Ce⁴⁺ oxidation states, reducing oxidative stress in OA joints (Corsi et al., 2023; Xiong et al., 2023). CeO₂NPs also inhibit NLRP3 inflammasome activation, which helps lower pro-inflammatory cytokines like IL-1β and IL-18 (Li et al., 2024a). Preclinical studies have shown that CeO₂NPs preserve cartilage integrity and improve joint function, with low cytotoxicity making them suitable for long-term use (Xiong et al., 2023). However, the technical challenges in producing precise CeO₂NPs and the need for further investigation into their long-term effects remain.

3.2.4 Zinc oxide nanoparticles

Zinc oxide nanoparticles (ZnONPs) present a promising approach to OA treatment due to their antioxidant and anti-inflammatory effects (Lopez-Miranda et al., 2023). They modulate the NF-κB pathway, decreasing the production of pro-inflammatory mediators such as MMPs and cytokines, while directly scavenging ROS to prevent oxidative damage in cartilage and synovial tissues (Azeez et al., 2024). ZnONPs also enhance chondrocyte survival and promote cartilage regeneration by upregulating anabolic factors and increasing antioxidant enzyme production (Li et al., 2020; Mirza et al., 2015). Zinc’s affordability and the non-toxic byproducts of ZnONP degradation make them an appealing option for large-scale therapeutic applications, though more research is needed to ensure their long-term safety in clinical settings (Eker et al., 2024).

3.3 Molecular OA therapies enhanced by nanotechnologies

Nanotechnologies, when combined with gene-specific inhibitors like siRNA and shRNA, represent a promising frontier in OA therapy (Rai et al., 2019). Nanoparticles enhance drug delivery by increasing stability, targeting capabilities, and sustaining therapeutic release. This results in more precise modulation of key OA drivers, such as inflammation, oxidative stress, and cartilage degradation. Below, we explore the technical applications of various molecular therapies, such as Protein Kinase D (PKD) inhibitors, p47phox, p66shc, and the peptide KAFAK inhibitors in combination with the nanoparticle systems (Kumari et al., 2023; Li et al., 2024b; Yan et al., 2019; Jeong et al., 2020).

3.3.1 Protein kinase D (PKD) inhibitors in nanoparticle systems

PKD is critical in regulating extracellular matrix (ECM) destruction and driving OA progression by activating the NF-κB pathway, which intensifies inflammation and matrix degradation (Baker et al., 2018). Nanoparticles, particularly PLGA, have been shown to deliver PKD inhibitors effectively, offering controlled and sustained release. This system enhances the inhibition of NF-κB activation and cytokine production (e.g., IL-1β), minimizing ECM degradation more effectively than free PKD inhibitors (Cho et al., 2019). Moreover, biomimetic nanoparticles, such as M2 macrophage-coated particles, exhibit enhanced targeting capabilities by mimicking immune responses, allowing for high concentrations of PKD inhibitors directly in inflamed joints, thereby reducing local inflammation. Biomimetic nanoparticles offer enhanced targeting of inflamed tissues, making them ideal for localized OA therapy (Cho et al., 2019; Rao and Shi, 2022). The choice of nanoparticle system should depend on the specific characteristics of the PKD inhibitor (e.g., hydrophobicity) and more clinical trials are needed for ideal therapeutic outcomes (e.g., sustained release, targeted delivery, or combination therapy) (Kumar et al., 2024; Tenchov et al., 2022; Yetisgin et al., 2020).

3.3.2 Peptide KAFAK inhibitors

KAFAK is a peptide known for suppressing pro-inflammatory cytokines, including IL-1β and IL-6, key factors in OA pathology (Bartlett et al., 2013). Nanoparticles coated with M2 macrophage membranes, incorporating KAFAK, have demonstrated precision in targeting inflamed joints (Zhou et al., 2023). By modifying these nanoparticles with iRGD peptides and hyaluronic acid, sustained release is achieved, leading to reduced inflammation and protection of cartilage (Zhou et al., 2023; Zhang S. et al., 2022). The use of macrophage membrane coatings enhances precise delivery to inflamed joints and immune evasion, increasing the therapeutic efficacy of KAFAK inhibitors. However, the potential immune response to foreign coatings may necessitate further optimization through complex clinical trials (Zheng et al., 2023).

3.3.3 shRNA-LEPR encapsulation in nanoparticle systems

The leptin receptor (LEPR) contributes to inflammation and cartilage breakdown in OA. Targeting LEPR with shRNA has proven effective in reducing its expression and mitigating inflammation. Biomimetic nanoparticles incorporating shRNA-LEPR, along with polyethylenimine (PEI) for gene delivery, offer sustained intra-articular release (Zhou et al., 2023; Li S. et al., 2024). Hyaluronic acid further enhances targeting to joint tissues, while M2 macrophage coatings improve localization in inflamed areas, efficient gene silencing on top of sustained release, leading to effective reduction in cartilage degradation (Li S. et al., 2024). However, long-term application maybe limited by the potential off-target effects, which could complicate the regulation of gene expression (Zha et al., 2021).

3.3.4 siRNA-p47phox in PLGA nanoparticles

The p47phox subunit of NADPH oxidase is involved in reactive oxygen species (ROS) production, contributing to OA-related oxidative stress and cartilage damage. Encapsulating siRNA-p47phox in PLGA nanoparticles provides sustained release, reducing ROS production and inflammation (Shin et al., 2020a). This system not only alleviates oxidative damage but also preserves cartilage integrity for a prolonged therapeutic effect. The limited stability of siRNA in biological environments has hindered its clinical application in OA treatment (Kumari et al., 2023).

3.3.5 siRNA-p66shc in nanoparticles

Overexpression of p66shc contributes to mitochondrial dysfunction and ROS overproduction in OA. Nanoparticles encapsulating siRNA-p66shc have shown efficacy in reducing ROS levels and inflammatory markers (e.g., IL-1β, TNF-α). By suppressing p66shc expression, these nanoparticles can modulate oxidative stress and inflammation, providing a targeted approach to slow OA progression (Shin et al., 2020b). Future studies should focus on optimizing the nanoparticle delivery efficiency and improving formulations stability (Liu et al., 2023a).

3.3.6 P16INK4a and synovial inflammation

P16INK4a, a cell cycle regulator, is upregulated in fibroblast-like synoviocytes (FLS) during OA, contributing to joint damage (Damerau et al., 2024). siRNA targeting P16INK4a, encapsulated in PLGA nanoparticles, accumulates in synovial tissues and reduces inflammation by lowering IL-1β levels in FLS, providing a localized therapeutic option for specific reduction of synovial inflammation (Park et al., 2022). However, challenges such as off-target effects and delivery efficiency to specific joint compartments remain obstacles for clinical applications (Kumari et al., 2023; Li et al., 2024b).

3.3.7 Black phosphorus nanosheets for cartilage and bone repair

Black phosphorus nanosheets represent a novel platform for OA treatment due to their pH-responsive behavior and ability to scavenge ROS (Zhang X. et al., 2022). These nanosheets promote cartilage regeneration and subchondral bone repair by protecting tissues from oxidative stress and modulating the joint’s inflammatory environment (Lu H. et al., 2023) (Table 1). However, research on black phosphorus nanosheet for OA treatment is still in the early-stages. Comprehensive clinical data are needed, particularly regarding sustained release, targeted delivery, combination therapies, and potential toxicity concerns (Zhuang et al., 2024).

In summary, nanoparticle-based delivery systems for molecular OA treatments offer numerous advantages, including enhanced targeting, sustained release, and reduced side effects. However, challenges such as off-target effects, nanoparticle stability, and scaling up for clinical applications remain. Future studies should prioritize optimizing nanoparticle formulations, enhancing bioavailability, and conducing long-term safety evaluations.

4 Nanomedicines for cartilage regeneration in OA

While inflammation plays a significant role in the progression of OA, regenerating damaged cartilage is key to achieving long-term disease modification (Knights et al., 2023). The unique challenges posed by cartilage, such as its avascularity and limited cellular repair mechanisms, make effective regeneration difficult (Van Osch et al., 2009; Jeyaraman et al., 2024; Roseti et al., 2019). Nanotechnology offers a promising avenue for overcoming these obstacles, providing innovative strategies that focus on cartilage repair and regeneration. In this chapter, we explore advanced nanomedicine approaches that aim to restore cartilage integrity, utilizing nanoparticles, scaffolds, and biologically active molecules for sustained, localized, and effective treatment (Eftekhari et al., 2020; Liang et al., 2023).

4.1 Key nanomedicines that promote cartilage regeneration

While inflammation is a significant contributor to OA progression, the ability to regenerate damaged cartilage remains a critical challenge in achieving meaningful disease modification (Roseti et al., 2019). Current pharmacological and surgical interventions often fail to fully restore articular cartilage due to the tissue’s limited self-repair capabilities. The avascular nature of cartilage, combined with its low density of chondrocytes, restricts its ability to recover from injury, leading to the gradual deterioration of joint function (Wang et al., 2024).

Traditional regenerative approaches, such as cell-based therapies and growth factor injections, have shown potential but are hampered by issues such as poor cell survival, lack of integration with native tissues, and the inability to control the precise delivery of therapeutic agents over time (Tsujii et al., 2024). These limitations highlight the need for advanced strategies that can enhance cartilage repair while ensuring sustained, localized effects (Wang et al., 2024).

Nanotechnology offers transformative solutions to these challenges by enabling the controlled and targeted delivery of bioactive molecules directly to sites of cartilage damage (Qiao et al., 2022). Nanomedicines can be engineered to deliver a variety of therapeutic agents—including growth factors, cytokines, and gene therapies—in a sustained manner, maximizing their efficacy (Liu et al., 2023b). Nanofibrous scaffolds, designed to mimic the extracellular matrix (ECM) of cartilage, provide structural support for cell attachment and proliferation. These scaffolds can be functionalized with growth factors or cells to further promote cartilage regeneration (Huang et al., 2024).

Key growth factors, such as transforming growth factor-beta (TGF-β) and bone morphogenetic proteins (BMPs), play pivotal roles in cartilage repair (Zhang X. et al., 2022; Wu et al., 2024). However, delivering these proteins effectively is challenging due to their short half-life and rapid degradation in the joint environment (Thielen et al., 2019). Nanoparticle carriers, such as PLGA nanoparticles combined with nanofibrous scaffolds, have demonstrated success in encapsulating these growth factors, providing sustained release while protecting them from degradation. These integrated nanotechnologies have been shown to stimulate chondrocyte activity more effectively, thereby enhancing cartilage regeneration (Chen et al., 2020; Qin et al., 2023).

Additionally, injectable hydrogels containing nanoparticles and cartilage-promoting factors can fill cartilage defects, offering both mechanical support and bioactivity. These hydrogels are often modified with materials like hyaluronic acid or collagen to better mimic the native cartilage environment. As they promote the growth of new cartilage tissue, they also integrate with existing tissues, with their biodegradability ensuring gradual replacement by natural tissue (Atwal et al., 2023; Carton and Malatesta, 2024).

4.2 Exosome-mimicking nanoparticles

Exosome-mimicking nanoparticles represent an innovative therapeutic strategy for OA by replicating the biological functions of natural exosomes, which are small cell-derived vesicles involved in intercellular communication and tissue repair (Chavda et al., 2023). These engineered nanoparticles hold promise in drug delivery, gene therapy, and tissue regeneration, offering targeted solutions for modulating the inflammatory and degenerative processes associated with OA (Li L. et al., 2024).

Natural exosomes, typically 30–150 nm in diameter, are secreted by various cell types such as mesenchymal stem cells (MSCs) and chondrocytes. They facilitate the transfer of bioactive molecules, including proteins, lipids, and RNA, which play critical roles in inflammation modulation and cartilage repair (Jiang et al., 2024). MSC-derived exosomes can promote chondrocyte migration and proliferation via the Mir-106b-5P/TIMP2 signaling pathway or activating YAP through the Wnt pathway (Tao et al., 2017; Tan et al., 2020). They can also reduce MMP13 and ADAMTS5 levels in chondrocytes, reverse mitochondrial membrane potential changes, and alleviate OA (Cosenza et al., 2017), potentially by inhibiting phosphorylation of p38 and ERK and promoting protein kinase B phosphorylation (Zhai et al., 2022). However, their clinical application faces challenges, such as low yield, heterogeneity, and instability during storage. Exosome-mimicking nanoparticles address these limitations by offering greater stability, scalability, and the ability to customize properties for specific therapeutic needs (Wang X. et al., 2022; Tan et al., 2024).

These nanoparticles are engineered to emulate the structural and functional characteristics of natural exosomes. Constructed from biodegradable materials like liposomes, polymeric nanoparticles, or silica nanoparticles, they are functionalized with surface proteins, ligands, or targeting molecules like hyaluronic acid or MSC-derived membrane proteins. These surface modifications enable the delivery of bioactive molecules, such as miRNAs or proteins, to stimulate cartilage regeneration without the complexity of direct stem cell therapies (Li Y.-J. et al., 2021). Several studies have shown the potential of exosome-mimicking nanoparticles in OA treatment. For instance, nanoparticles mimicking exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs), loaded with growth factors and RNA molecules, have been shown to reduce cartilage degradation, improve joint function, and lower pro-inflammatory cytokine levels in OA models (Cosenza et al., 2017). Additionally, HA-coated exosome-mimicking nanoparticles have demonstrated effective delivery of siRNA targeting MMP13—an enzyme involved in cartilage breakdown—leading to enhanced cartilage preservation in animal studies (Kumari et al., 2023; Qiu et al., 2013) (Table 2).

4.3 Mesenchymal stem cells in nanoparticle therapy

Nanoparticle-encapsulated mesenchymal stem cell (MSC) therapy is a promising new approach for OA treatment, combining the regenerative capabilities of MSCs with the advantages of nanoparticles, such as targeted delivery and enhanced stability (Ding et al., 2022; Bunnell, 2021; Mizuno et al., 2022; Hoang et al., 2022). This method addresses key limitations of traditional MSC-based therapies, such as low cell survival, poor retention in joint tissues, and insufficient targeting (Zou et al., 2023). By using nanoparticles, the therapeutic potential of MSCs in cartilage repair, inflammation modulation, and slowing OA progression is significantly enhanced (Cai et al., 2023).

MSCs are multipotent cells that can differentiate into chondrocytes, the cells responsible for maintaining cartilage integrity. This chondrogenic potential is linked to the upregulation of SOX9, a key marker for chondrocyte progenitors (Zhao et al., 2017). MSCs also secrete bioactive molecules like TGF-β and BMP, which promote bone formation and increase extracellular matrix (ECM) production by inducing SOX9 expression (Cai et al., 2023; Du et al., 2023). Studies have shown that MSC injections can restore chondrocyte proliferation, inhibit apoptosis, regulate inflammation, and help ki67 expression in damaged cartilage (Zhang et al., 2021) (Figure 3). However, despite these benefits, MSCs often exhibit poor retention and rapid degradation after intra-articular injection, limiting their therapeutic efficacy.

FIGURE 3

To overcome these challenges, various types of nanoparticles are being investigated to encapsulate MSCs or their secreted products. These include polymeric nanoparticles, liposomes, and hydrogels. For example, PLGA nanoparticles have been used to encapsulate MSCs or MSC-derived exosomes, promoting chondrocyte proliferation and enhancing cartilage matrix production. In preclinical models, this approach has shown potential in reducing cartilage degradation (Fan et al., 2006). Nanoparticles can also deliver anti-inflammatory cytokines, such as IL-10 and TGF-β, in a controlled manner, leading to reduced synovitis and cartilage destruction. While most research in nanoparticle-encapsulated MSC therapy remains at the preclinical stage, early results in animal models are promising (Gonzalez-Fernandez et al., 2022). These studies demonstrate improved cartilage regeneration, reduced inflammation, and better joint function. However, further investigation is required to optimize nanoparticle formulations, ensure long-term safety, and assess the clinical efficacy of these therapies in human OA patients (Seo et al., 2022).

5 Conclusion: Recent advances in nanotechnologies for OA treatment

Recent advancements in nanotechnologies offer promising avenues for overcoming the limitations of traditional OA therapies. Nanoparticles have been utilized as vectors to improve the delivery, bioavailability, and stability of existing OA treatments, such as NSAIDs, by enabling targeted, sustained release directly into the inflamed joints. Metal-based nanoparticles, particularly those leveraging silver and copper, have shown potential in reducing oxidative stress, though concerns about toxicity and cost remain.

The combination of nanoparticles with molecular agents, including peptides, siRNA, and shRNA, further enhances the therapeutic potential by allowing for precise targeting of inflammation, oxidative stress, and cartilage degradation at the molecular level. Additionally, nanomedicines designed to promote cartilage regeneration, such as black phosphorus nanosheets, represent a breakthrough in the tissue repair process. Another emerging area is the encapsulation of mesenchymal stem cells (MSCs) in nanoparticles, which improves the efficacy of stem cell therapies in repairing joint tissues and reducing inflammation.

While these nanotechnologies demonstrate significant promise, their clinical applications are still in early stages, with most studies focusing on animal models. Continued research is essential to address challenges related to nanoparticle safety, long-term effects, and scaling up for clinical use. Future directions will likely involve refining nanoparticle formulations for better bioavailability, stability, and minimizing off-target effects, ensuring that nanomedicine becomes a transformative tool in OA management.

References

• 1

  Abdel-Aziz M. A. Ahmed H. M. S. El-Nekeety A. A. Sharaf H. A. Abdel-Aziem S. H. Abdel-Wahhab M. A. (2021). Biosynthesis of gold nanoparticles for the treatment of osteoarthritis alone or in combination with Diacerein® in a rat model. Inflammopharmacology29, 705–719. 10.1007/s10787-021-00833-8

  • CrossRef
  • Google Scholar

• 2

  Ahmadi M. Bekeschus S. Weltmann K.-D. Von Woedtke T. Wende K. (2022). Non-steroidal anti-inflammatory drugs: recent advances in the use of synthetic COX-2 inhibitors. RSC Med. Chem.13, 471–496. 10.1039/d1md00280e

  • CrossRef
  • Google Scholar

• 3

  Akhileshwar Jha L. Imran M. Shrestha J. Prasad Devkota H. Bhattacharya K. Alsayari A. et al (2024). Effectiveness of phytoconstituents and potential of phyto-nanomedicines combination to treat osteoarthritis. Eur. Polym. J.215, 113243. 10.1016/j.eurpolymj.2024.113243

  • CrossRef
  • Google Scholar

• 4

  Akter M. Sikder M. T. Rahman M. M. Ullah A. K. M. A. Hossain K. F. B. Banik S. et al (2018). A systematic review on silver nanoparticles-induced cytotoxicity: physicochemical properties and perspectives. J. Adv. Res.9, 1–16. 10.1016/j.jare.2017.10.008

  • CrossRef
  • Google Scholar

• 5

  Alcantara K. P. Malabanan J. W. T. Nalinratana N. Thitikornpong W. Rojsitthisak P. Rojsitthisak P. (2024). Cannabidiol-loaded solid lipid nanoparticles ameliorate the inhibition of proinflammatory cytokines and free radicals in an in vitro inflammation-induced cell model. Int. J. Mol. Sci.25, 4744. 10.3390/ijms25094744

  • CrossRef
  • Google Scholar

• 6

  Aldrich J. L. Panicker A. Ovalle R. Sharma B. (2023). Drug delivery strategies and nanozyme technologies to overcome limitations for targeting oxidative stress in osteoarthritis. Pharmaceuticals16, 1044. 10.3390/ph16071044

  • CrossRef
  • Google Scholar

• 7

  Altman R. Manjoo A. Fierlinger A. Niazi F. Nicholls M. (2015). The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet. Disord.16, 321. 10.1186/s12891-015-0775-z

  • CrossRef
  • Google Scholar

• 8

  Alvarez-Soria M. A. Largo R. Santillana J. Sánchez-Pernaute O. Calvo E. Hernández M. et al (2006). Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac. Ann. Rheum. Dis.65, 998–1005. 10.1136/ard.2005.046920

  • CrossRef
  • Google Scholar

• 9

  Ansari M. Y. Ahmad N. Haqqi T. M. (2020). Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols. Biomed. Pharmacother.129, 110452. 10.1016/j.biopha.2020.110452

  • CrossRef
  • Google Scholar

• 10

  Ashfaq R. Rasul A. Asghar S. Kovács A. Berkó S. Budai-Szűcs M. (2023). Lipid nanoparticles: an effective tool to improve the bioavailability of nutraceuticals. Int. J. Mol. Sci.24, 15764. 10.3390/ijms242115764

  • CrossRef
  • Google Scholar

• 11

  Assadpour E. Rezaei A. Das S. S. Krishna Rao B. V. Singh S. K. Kharazmi M. S. et al (2023). Cannabidiol-loaded nanocarriers and their therapeutic applications. Pharmaceuticals16, 487. 10.3390/ph16040487

  • CrossRef
  • Google Scholar

• 12

  Atwal A. Dale T. P. Snow M. Forsyth N. R. Davoodi P. (2023). Injectable hydrogels: an emerging therapeutic strategy for cartilage regeneration. Adv. Colloid Interface Sci.321, 103030. 10.1016/j.cis.2023.103030

  • CrossRef
  • Google Scholar

• 13

  Azeez S. Fatima M. Gul O. Rehman H. Shad M. A. Nawaz H. (2024). Zinc oxide nanoparticles-doped curcumin-assisted recovery of rheumatoid arthritis and antioxidant status in experimental rabbits. BioMedicine14, 49–59. 10.37796/2211-8039.1446

  • CrossRef
  • Google Scholar

• 14

  Badri W. Miladi K. Nazari Q. A. Greige-Gerges H. Fessi H. Elaissari A. (2016). Encapsulation of NSAIDs for inflammation management: overview, progress, challenges and prospects. Int. J. Pharm.515, 757–773. 10.1016/j.ijpharm.2016.11.002

  • CrossRef
  • Google Scholar

• 15

  Baek J.-S. Yeo E. W. Lee Y. H. Tan N. S. Loo S. C. (2017). Controlled-release nanoencapsulating microcapsules to combat inflammatory diseases. Drug Des. devel. Ther.11, 1707–1717. 10.2147/DDDT.S133344

  • CrossRef
  • Google Scholar

• 16

  Bai H. Yuan R. Zhang Z. Liu L. Wang X. Song X. et al (2021). Intra‐articular injection of baicalein inhibits cartilage catabolism and NLRP3 inflammasome signaling in a posttraumatic OA model. Oxid. Med. Cell. Longev.2021, 6116890. 10.1155/2021/6116890

  • CrossRef
  • Google Scholar

• 17

  Baker J. Falconer A. M. D. Wilkinson D. J. Europe-Finner G. N. Litherland G. J. Rowan A. D. (2018). Protein kinase D3 modulates MMP1 and MMP13 expression in human chondrocytes. PLOS ONE13, e0195864. 10.1371/journal.pone.0195864

  • CrossRef
  • Google Scholar

• 18

  Ban C. Jo M. Park Y. H. Kim J. H. Han J. Y. Lee K. W. et al (2020). Enhancing the oral bioavailability of curcumin using solid lipid nanoparticles. Food Chem.302, 125328. 10.1016/j.foodchem.2019.125328

  • CrossRef
  • Google Scholar

• 19

  Bartlett R. L. Sharma S. Panitch A. (2013). Cell-penetrating peptides released from thermosensitive nanoparticles suppress pro-inflammatory cytokine response by specifically targeting inflamed cartilage explants. Nanomedicine Nanotechnol. Biol. Med.9, 419–427. 10.1016/j.nano.2012.09.003

  • CrossRef
  • Google Scholar

• 20

  Bernetti A. Mangone M. Villani C. Alviti F. Valeo M. Grassi M. C. et al (2019). Appropriateness of clinical criteria for the use of SYmptomatic slow-acting drug for OsteoArthritis (sysadoa). A delphi method consensus initiative among experts in Italy. Eur. J. Phys. Rehabil. Med.55, 658–664. 10.23736/S1973-9087.19.05633-8

  • CrossRef
  • Google Scholar

• 21

  Bigaj-Józefowska M. J. Grześkowiak B. F. (2022). Polymeric nanoparticles wrapped in biological membranes for targeted anticancer treatment. Eur. Polym. J.176, 111427. 10.1016/j.eurpolymj.2022.111427

  • CrossRef
  • Google Scholar

• 22

  Boehme K. A. Rolauffs B. (2018). Onset and progression of human osteoarthritis—can growth factors, inflammatory cytokines, or differential miRNA expression concomitantly induce proliferation, ECM degradation, and inflammation in articular cartilage?Int. J. Mol. Sci.19, 2282. 10.3390/ijms19082282

  • CrossRef
  • Google Scholar

• 23

  Boehnke N. Straehla J. P. Safford H. C. Kocak M. Rees M. G. Ronan M. et al (2022). Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery. Science377, eabm5551. 10.1126/science.abm5551

  • CrossRef
  • Google Scholar

• 24

  Börner F. Werner M. Ertelt J. Meins J. Abdel-Tawab M. Werz O. (2021). Analysis of boswellic acid contents and related pharmacological activities of frankincense-based remedies that modulate inflammation. Pharmaceuticals14, 660. 10.3390/ph14070660

  • CrossRef
  • Google Scholar

• 25

  Borrajo M. L. Lou G. Anthiya S. Lapuhs P. Álvarez D. M. Tobío A. et al (2024). Nanoemulsions and nanocapsules as carriers for the development of intranasal mRNA vaccines. Drug Deliv. Transl. Res.14, 2046–2061. 10.1007/s13346-024-01635-5

  • CrossRef
  • Google Scholar

• 26

  Bryk M. Starowicz K. (2021). Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: an updated review. Pharmacol. Rep.73, 681–699. 10.1007/s43440-021-00270-y

  • CrossRef
  • Google Scholar

• 27

  Buhrmann C. Brockmueller A. Mueller A.-L. Shayan P. Shakibaei M. (2021). Curcumin attenuates environment-derived osteoarthritis by Sox9/NF-kB signaling Axis. Int. J. Mol. Sci.22, 7645. 10.3390/ijms22147645

  • CrossRef
  • Google Scholar

• 28

  Bunnell B. A. (2021). Adipose tissue-derived mesenchymal stem cells. Cells10, 3433. 10.3390/cells10123433

  • CrossRef
  • Google Scholar

• 29

  Busa P. Lee S.-O. Huang N. Kuthati Y. Wong C.-S. (2022). Carnosine alleviates knee osteoarthritis and promotes synoviocyte protection via activating the Nrf2/HO-1 signaling pathway: an in-vivo and in-vitro study. Antioxidants11, 1209. 10.3390/antiox11061209

  • CrossRef
  • Google Scholar

• 30

  Cai Y. Wu C. Ou Q. Zeng M. Xue S. Chen J. et al (2023). Enhanced osteoarthritis therapy by nanoengineered mesenchymal stem cells using biomimetic CuS nanoparticles loaded with plasmid DNA encoding TGF-β1. Bioact. Mater.19, 444–457. 10.1016/j.bioactmat.2022.04.021

  • CrossRef
  • Google Scholar

• 31

  Cao F. Gui S. Y. Gao X. Zhang W. Fu Z. Y. Tao L. M. et al (2022). Research progress of natural product-based nanomaterials for the treatment of inflammation-related diseases. Mater. Des.218, 110686. 10.1016/j.matdes.2022.110686

  • CrossRef
  • Google Scholar

• 32

  Carrillo-Martinez E. J. Flores-Hernández F. Y. Salazar-Montes A. M. Nario-Chaidez H. F. Quercetin L. D. (2024). Quercetin, a flavonoid with great pharmacological capacity. Molecules29, 1000. 10.3390/molecules29051000

  • CrossRef
  • Google Scholar

• 33

  Carton F. Malatesta M. (2024). Nanotechnological research for regenerative medicine: the role of hyaluronic acid. Int. J. Mol. Sci.25, 3975. 10.3390/ijms25073975

  • CrossRef
  • Google Scholar

• 34

  Chavda S. Rabbani S. A. Wadhwa T. (2022). Role and effectiveness of intra-articular injection of hyaluronic acid in the treatment of knee osteoarthritis: a systematic review. Cureus14, e24503. 10.7759/cureus.24503

  • CrossRef
  • Google Scholar

• 35

  Chavda V. P. Pandya A. Kumar L. Raval N. Vora L. K. Pulakkat S. et al (2023). Exosome nanovesicles: a potential carrier for therapeutic delivery. Nano Today49, 101771. 10.1016/j.nantod.2023.101771

  • CrossRef
  • Google Scholar

• 36

  Chen L. Liu J. Guan M. Zhou T. Duan X. Xiang Z. (2020). Growth factor and its polymer scaffold-based delivery system for cartilage tissue engineering. Int. J. Nanomedicine15, 6097–6111. 10.2147/IJN.S249829

  • CrossRef
  • Google Scholar

• 37

  Chen M. Li L. Wang Z. Li P. Feng F. Zheng X. (2019). High molecular weight hyaluronic acid regulates P. gingivalis–induced inflammation and migration in human gingival fibroblasts via MAPK and NF-κB signaling pathway. Arch. Oral Biol.98, 75–80. 10.1016/j.archoralbio.2018.10.027

  • CrossRef
  • Google Scholar

• 38

  Chen W. Jin G. J. Xiong Y. Hu P. F. Bao J. P. Wu L. D. (2018). Rosmarinic acid down‐regulates NO and PGE 2 expression via MAPK pathway in rat chondrocytes. J. Cell. Mol. Med.22, 346–353. 10.1111/jcmm.13322

  • CrossRef
  • Google Scholar

• 39

  Cheng X. Xie Q. Sun Y. (2023). Advances in nanomaterial-based targeted drug delivery systems. Front. Bioeng. Biotechnol.11, 1177151. 10.3389/fbioe.2023.1177151

  • CrossRef
  • Google Scholar

• 40

  Chevalier X. Goupille P. Beaulieu A. D. Burch F. X. Bensen W. G. Conrozier T. et al (2009). Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double‐blind, placebo‐controlled study. Arthritis Care Res.61, 344–352. 10.1002/art.24096

  • CrossRef
  • Google Scholar

• 41

  Cho H. Bhatti F.-U.-R. Hasty K. A. Yi A.-K. (2019). Nanosome-Mediated delivery of protein kinase D inhibitor protects chondrocytes from interleukin-1β-induced stress and apoptotic death. Int. J. Nanomedicine14, 8835–8846. 10.2147/IJN.S218901

  • CrossRef
  • Google Scholar

• 42

  Choi S. J. McClements D. J. (2020). Nanoemulsions as delivery systems for lipophilic nutraceuticals: strategies for improving their formulation, stability, functionality and bioavailability. Food Sci. Biotechnol.29, 149–168. 10.1007/s10068-019-00731-4

  • CrossRef
  • Google Scholar

• 43

  Chow Y. Y. Chin K.-Y. (2020). The role of inflammation in the pathogenesis of osteoarthritis. Mediat. Inflamm.2020, 8293921. 10.1155/2020/8293921

  • CrossRef
  • Google Scholar

• 44

  Chuang S.-Y. Lin C.-H. Huang T.-H. Fang J.-Y. (2018). Lipid-based nanoparticles as a potential delivery approach in the treatment of rheumatoid arthritis. Nanomaterials8, 42. 10.3390/nano8010042

  • CrossRef
  • Google Scholar

• 45

  Colletti A. Cicero A. F. G. (2021). Nutraceutical approach to chronic osteoarthritis: from molecular research to clinical evidence. Int. J. Mol. Sci.22, 12920. 10.3390/ijms222312920

  • CrossRef
  • Google Scholar

• 46

  Conaghan P. G. Cook A. D. Hamilton J. A. Tak P. P. (2019). Therapeutic options for targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol.15, 355–363. 10.1038/s41584-019-0221-y

  • CrossRef
  • Google Scholar

• 47

  Cooper C. Chapurlat R. Al-Daghri N. Herrero-Beaumont G. Bruyère O. Rannou F. et al (2019). Safety of oral non-selective non-steroidal anti-inflammatory drugs in osteoarthritis: what does the literature say?Drugs Aging36, 15–24. 10.1007/s40266-019-00660-1

  • CrossRef
  • Google Scholar

• 48

  Corsi F. Deidda Tarquini G. Urbani M. Bejarano I. Traversa E. Ghibelli L. (2023). The impressive anti-inflammatory activity of cerium oxide nanoparticles: more than redox?Nanomaterials13, 2803. 10.3390/nano13202803

  • CrossRef
  • Google Scholar

• 49

  Cosenza S. Ruiz M. Toupet K. Jorgensen C. Noël D. (2017). Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci. Rep.7, 16214. 10.1038/s41598-017-15376-8

  • CrossRef
  • Google Scholar

• 50

  Crivelli B. Bari E. Perteghella S. Catenacci L. Sorrenti M. Mocchi M. et al (2019). Silk fibroin nanoparticles for celecoxib and curcumin delivery: ROS-scavenging and anti-inflammatory activities in an in vitro model of osteoarthritis. Eur. J. Pharm. Biopharm.137, 37–45. 10.1016/j.ejpb.2019.02.008

  • CrossRef
  • Google Scholar

• 51

  Damerau A. Rosenow E. Alkhoury D. Buttgereit F. Gaber T. (2024). Fibrotic pathways and fibroblast-like synoviocyte phenotypes in osteoarthritis. Front. Immunol.15, 1385006. 10.3389/fimmu.2024.1385006

  • CrossRef
  • Google Scholar

• 52

  De Faro Silva R. Barreto A. S. Trindade G. d. G. G. Lima C. M. Araújo A. A. d. S. Menezes I. R. A. et al (2022). Enhancement of the functionality of women with knee osteoarthritis by a gel formulation with Caryocar coriaceum Wittm (“Pequi”) nanoencapsulated pulp fixed oil. Biomed. Pharmacother.150, 112938. 10.1016/j.biopha.2022.112938

  • CrossRef
  • Google Scholar

• 53

  Dhall A. Self W. (2018). Cerium oxide nanoparticles: a brief review of their synthesis methods and biomedical applications. Antioxidants7, 97. 10.3390/antiox7080097

  • CrossRef
  • Google Scholar

• 54

  Dilliard S. A. Cheng Q. Siegwart D. J. (2021). On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles. Proc. Natl. Acad. Sci.118, e2109256118. 10.1073/pnas.2109256118

  • CrossRef
  • Google Scholar

• 55

  Ding P. Gao C. Gao Y. Liu D. Li H. Xu J. et al (2022). Osteocytes regulate senescence of bone and bone marrow. eLife11, e81480. 10.7554/eLife.81480

  • CrossRef
  • Google Scholar

• 56

  Dou Y. Li C. Li L. Guo J. Zhang J. (2020). Bioresponsive drug delivery systems for the treatment of inflammatory diseases. J. Control. Release327, 641–666. 10.1016/j.jconrel.2020.09.008

  • CrossRef
  • Google Scholar

• 57

  Du X. Cai L. Xie J. Zhou X. (2023). The role of TGF-beta3 in cartilage development and osteoarthritis. Bone Res.11, 2. 10.1038/s41413-022-00239-4

  • CrossRef
  • Google Scholar

• 58

  Duan W.-L. Zhang L. N. Bohara R. Martin-Saldaña S. Yang F. Zhao Y. Y. et al (2023). Adhesive hydrogels in osteoarthritis: from design to application. Mil. Med. Res.10, 4. 10.1186/s40779-022-00439-3

  • CrossRef
  • Google Scholar

• 59

  Ebert J. R. Joss B. Jardine B. Wood D. J. (2013). Randomized trial investigating the efficacy of manual lymphatic drainage to improve early outcome after total knee arthroplasty. Arch. Phys. Med. Rehabil.94, 2103–2111. 10.1016/j.apmr.2013.06.009

  • CrossRef
  • Google Scholar

• 60

  Eftekhari A. Maleki Dizaj S. Sharifi S. Salatin S. Rahbar Saadat Y. Zununi Vahed S. et al (2020). The use of nanomaterials in tissue engineering for cartilage regeneration; current approaches and future perspectives. Int. J. Mol. Sci.21, 536. 10.3390/ijms21020536

  • CrossRef
  • Google Scholar

• 61

  Eisenstein A. Hilliard B. K. Pope S. D. Zhang C. Taskar P. Waizman D. A. et al (2022). Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity55, 1082–1095.e5. 10.1016/j.immuni.2022.04.015

  • CrossRef
  • Google Scholar

• 62

  Eker F. Duman H. Akdaşçi E. Bolat E. Sarıtaş S. Karav S. et al (2024). A comprehensive review of nanoparticles: from classification to application and toxicity. Molecules29, 3482. 10.3390/molecules29153482

  • CrossRef
  • Google Scholar

• 63

  Emami A. Tepper J. Short B. Yaksh T. L. Bendele A. M. Ramani T. et al (2018). Toxicology evaluation of drugs administered via uncommon routes: intranasal, intraocular, intrathecal/intraspinal, and intra-articular. Int. J. Toxicol.37, 4–27. 10.1177/1091581817741840

  • CrossRef
  • Google Scholar

• 64

  Evans C. H. Kraus V. B. Setton L. A. (2014). Progress in intra-articular therapy. Nat. Rev. Rheumatol.10, 11–22. 10.1038/nrrheum.2013.159

  • CrossRef
  • Google Scholar

• 65

  Fan H. Hu Y. Zhang C. Li X. Lv R. Qin L. et al (2006). Cartilage regeneration using mesenchymal stem cells and a PLGA–gelatin/chondroitin/hyaluronate hybrid scaffold. Biomaterials27, 4573–4580. 10.1016/j.biomaterials.2006.04.013

  • CrossRef
  • Google Scholar

• 66

  Fang S. Zhang B. Xiang W. Zheng L. Wang X. Li S. et al (2024). Natural products in osteoarthritis treatment: bridging basic research to clinical applications. Chin. Med.19, 25. 10.1186/s13020-024-00899-w

  • CrossRef
  • Google Scholar

• 67

  Ferdous Z. Nemmar A. (2020). Health impact of silver nanoparticles: a review of the biodistribution and toxicity following various routes of exposure. Int. J. Mol. Sci.21, 2375. 10.3390/ijms21072375

  • CrossRef
  • Google Scholar

• 68

  Filardo G. Di Matteo B. Di Martino A. Merli M. L. Cenacchi A. Fornasari P. et al (2015). Platelet-rich plasma intra-articular knee injections show No superiority versus viscosupplementation: a randomized controlled trial. Am. J. Sports Med.43, 1575–1582. 10.1177/0363546515582027

  • CrossRef
  • Google Scholar

• 69

  Fine P. G. Rosenfeld M. J. (2013). The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med. J.4, e0022. 10.5041/RMMJ.10129

  • CrossRef
  • Google Scholar

• 70

  Foell D. Wittkowski H. Roth J. (2007). Mechanisms of Disease: a ‘DAMP’ view of inflammatory arthritis. Nat. Clin. Pract. Rheumatol.3, 382–390. 10.1038/ncprheum0531

  • CrossRef
  • Google Scholar

• 71

  Furtado M. Chen L. Chen Z. Chen A. Cui W. (2022). Development of fish collagen in tissue regeneration and drug delivery. Eng. Regen.3, 217–231. 10.1016/j.engreg.2022.05.002

  • CrossRef
  • Google Scholar

• 72

  Gaio E. Conte C. Esposito D. Reddi E. Quaglia F. Moret F. (2020). CD44 targeting mediated by polymeric nanoparticles and combination of chlorine TPCS2a-PDT and docetaxel-chemotherapy for efficient killing of breast differentiated and stem cancer cells in vitro. Cancers12, 278. 10.3390/cancers12020278

  • CrossRef
  • Google Scholar

• 73

  Gan J. Deng X. Le Y. Lai J. Liao X. (2023). The development of naringin for use against bone and cartilage disorders. Molecules28, 3716. 10.3390/molecules28093716

  • CrossRef
  • Google Scholar

• 74

  Gan X. Wang X. Huang Y. Li G. Kang H. (2024). Applications of hydrogels in osteoarthritis treatment. Biomedicines12, 923. 10.3390/biomedicines12040923

  • CrossRef
  • Google Scholar

• 75

  Gao Z.-R. Feng Y. Z. Zhao Y. Q. Zhao J. Zhou Y. H. Ye Q. et al (2022). Traditional Chinese medicine promotes bone regeneration in bone tissue engineering. Chin. Med.17, 86. 10.1186/s13020-022-00640-5

  • CrossRef
  • Google Scholar

• 76

  Ghasemiyeh P. Mohammadi-Samani S. (2018). Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages. Res. Pharm. Sci.13, 288–303. 10.4103/1735-5362.235156

  • CrossRef
  • Google Scholar

• 77

  Gherasim O. Puiu R. A. Bîrcă A. C. Burdușel A.-C. Grumezescu A. M. (2020). An updated review on silver nanoparticles in biomedicine. Nanomaterials10, 2318. 10.3390/nano10112318

  • CrossRef
  • Google Scholar

• 78

  Gomaa A. A. Mohamed H. S. Abd-ellatief R. B. Gomaa M. A. (2021). Boswellic acids/Boswellia serrata extract as a potential COVID-19 therapeutic agent in the elderly. Inflammopharmacology29, 1033–1048. 10.1007/s10787-021-00841-8

  • CrossRef
  • Google Scholar

• 79

  Gonzalez-Fernandez P. Rodríguez-Nogales C. Jordan O. Allémann E. (2022). Combination of mesenchymal stem cells and bioactive molecules in hydrogels for osteoarthritis treatment. Eur. J. Pharm. Biopharm.172, 41–52. 10.1016/j.ejpb.2022.01.003

  • CrossRef
  • Google Scholar

• 80

  Guan T. Ding L. G. Lu B. Y. Guo J. Y. Wu M. Y. Tan Z. Q. et al (2022). Combined administration of curcumin and chondroitin sulfate alleviates cartilage injury and inflammation via NF-κB pathway in knee osteoarthritis rats. Front. Pharmacol.13, 882304. 10.3389/fphar.2022.882304

  • CrossRef
  • Google Scholar

• 81

  Guilak F. Nims R. J. Dicks A. Wu C.-L. Meulenbelt I. (2018). Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol.71–72, 40–50. 10.1016/j.matbio.2018.05.008

  • CrossRef
  • Google Scholar

• 82

  Guo X. Wang L. Xu M. Bai J. Shen J. Yu B. et al (2018). Shikimic acid prevents cartilage matrix destruction in human chondrocytes. Int. Immunopharmacol.63, 155–160. 10.1016/j.intimp.2018.07.021

  • CrossRef
  • Google Scholar

• 83

  Gupta A. Costa A. P. Xu X. Lee S. L. Cruz C. N. Bao Q. et al (2020). Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing. Int. J. Pharm.583, 119340. 10.1016/j.ijpharm.2020.119340

  • CrossRef
  • Google Scholar

• 84

  Han H. S. Koo S. Y. Choi K. Y. (2022). Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging. Bioact. Mater.14, 182–205. 10.1016/j.bioactmat.2021.11.027

  • CrossRef
  • Google Scholar

• 85

  Han Y. Huang S. (2023). Nanomedicine is more than a supporting role in rheumatoid arthritis therapy. J. Control. Release356, 142–161. 10.1016/j.jconrel.2023.02.035

  • CrossRef
  • Google Scholar

• 86

  Hassan M. H. Ghobara M. M. (2016). Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress. Naunyn. Schmiedeb. Arch. Pharmacol.389, 971–983. 10.1007/s00210-016-1263-1

  • CrossRef
  • Google Scholar

• 87

  He J. Ma Y. Niu X. Pei J. Yan R. Xu F. et al (2024). Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: the protective role of N-acetylcysteine. Toxicology502, 153734. 10.1016/j.tox.2024.153734

  • CrossRef
  • Google Scholar

• 88

  He M. Qin Z. Liang X. He X. Zhu B. Lu Z. et al (2021). A pH-responsive mesoporous silica nanoparticles-based drug delivery system with controlled release of andrographolide for OA treatment. Regen. Biomater.8, rbab020. 10.1093/rb/rbab020

  • CrossRef
  • Google Scholar

• 89

  Hoang D. M. Pham P. T. Bach T. Q. Ngo A. T. L. Nguyen Q. T. Phan T. T. K. et al (2022). Stem cell-based therapy for human diseases. Signal Transduct. Target. Ther.7, 272. 10.1038/s41392-022-01134-4

  • CrossRef
  • Google Scholar

• 90

  Hodgkinson T. Kelly D. C. Curtin C. M. O’Brien F. J. (2022). Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat. Rev. Rheumatol.18, 67–84. 10.1038/s41584-021-00724-w

  • CrossRef
  • Google Scholar

• 91

  Hou S.-M. Chen P. C. Lin C. M. Fang M. L. Chi M. C. Liu J. F. (2020). CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK, and AP-1 pathway. Arthritis Res. Ther.22, 251. 10.1186/s13075-020-02331-8

  • CrossRef
  • Google Scholar

• 92

  Householder N. A. Raghuram A. Agyare K. Thipaphay S. Zumwalt M. (2023). A review of recent innovations in cartilage regeneration strategies for the treatment of primary osteoarthritis of the knee: intra-articular injections. Orthop. J. Sports Med.11, 23259671231155950. 10.1177/23259671231155950

  • CrossRef
  • Google Scholar

• 93

  Hsu C.-Y. Rheima A. M. Kadhim M. M. Ahmed N. N. Mohammed S. H. Abbas F. H. et al (2023). An overview of nanoparticles in drug delivery: properties and applications. South Afr. J. Chem. Eng.46, 233–270. 10.1016/j.sajce.2023.08.009

  • CrossRef
  • Google Scholar

• 94

  Hu B. Ga F. Li C. Zhang B. An M. Lu M. et al (2020). Rhein laden pH-responsive polymeric nanoparticles for treatment of osteoarthritis. Amb. Express10, 158. 10.1186/s13568-020-01095-3

  • CrossRef
  • Google Scholar

• 95

  Hu W. Chen Y. Dou C. Dong S. (2021). Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis. Ann. Rheum. Dis.80, 413–422. 10.1136/annrheumdis-2020-218089

  • CrossRef
  • Google Scholar

• 96

  Hu Y. Gui Z. Zhou Y. Xia L. Lin K. Xu Y. (2019). Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic. Biol. Med.145, 146–160. 10.1016/j.freeradbiomed.2019.09.024

  • CrossRef
  • Google Scholar

• 97

  Hu Z. Guan Y. Hu W. Xu Z. Ishfaq M. (2022). An overview of pharmacological activities of baicalin and its aglycone baicalein: new insights into molecular mechanisms and signaling pathways. Iran. J. Basic Med. Sci.25, 14–26. 10.22038/ijbms.2022.60380.13381

  • CrossRef
  • Google Scholar

• 98

  Huang H. Lou Z. Zheng S. Wu J. Yao Q. Chen R. et al (2022). Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage. Drug Deliv.29, 767–791. 10.1080/10717544.2022.2048130

  • CrossRef
  • Google Scholar

• 99

  Huang T. Liu Y. Zhang C. (2019). Pharmacokinetics and bioavailability enhancement of baicalin: a review. Eur. J. Drug Metab. Pharmacokinet.44, 159–168. 10.1007/s13318-018-0509-3

  • CrossRef
  • Google Scholar

• 100

  Huang Y. Guo X. Wu Y. Chen X. Feng L. Xie N. et al (2024). Nanotechnology’s frontier in combatting infectious and inflammatory diseases: prevention and treatment. Signal Transduct. Target. Ther.9, 34. 10.1038/s41392-024-01745-z

  • CrossRef
  • Google Scholar

• 101

  Hügle T. Nasi S. Ehirchiou D. Omoumi P. Busso N. (2022). Fibrin deposition associates with cartilage degeneration in arthritis. eBioMedicine81, 104081. 10.1016/j.ebiom.2022.104081

  • CrossRef
  • Google Scholar

• 102

  Hunter D. J. March L. Chew M. (2020). Osteoarthritis in 2020 and beyond: a lancet commission. Lancet396, 1711–1712. 10.1016/S0140-6736(20)32230-3

  • CrossRef
  • Google Scholar

• 103

  Janowicz P. W. Houston Z. H. Bunt J. Fletcher N. L. Bell C. A. Cowin G. et al (2022). Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption. Biomaterials283, 121416. 10.1016/j.biomaterials.2022.121416

  • CrossRef
  • Google Scholar

• 104

  Jargin S. V. (2012). Supplementation of glycosaminoglycans and their precursors in osteoarthritis versus diet modification. Int. J. Rheum. Dis.15, e45–e46. 10.1111/j.1756-185X.2012.01707.x

  • CrossRef
  • Google Scholar

• 105

  Jennings C. L. Dziubla T. D. Puleo D. A. (2016). Combined effects of drugs and plasticizers on the properties of drug delivery films. J. Bioact. Compat. Polym.31, 323–333. 10.1177/0883911515627178

  • CrossRef
  • Google Scholar

• 106

  Jeong S. Kang M. Park J. Im G. (2020). Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment. J. Biomed. Mater. Res. B Appl. Biomater.108, 234–242. 10.1002/jbm.b.34383

  • CrossRef
  • Google Scholar

• 107

  Jeyaraman M. Jeyaraman N. Nallakumarasamy A. Ramasubramanian S. Yadav S. (2024). Critical challenges and frontiers in cartilage tissue engineering. Cureus16, e53095. 10.7759/cureus.53095

  • CrossRef
  • Google Scholar

• 108

  Jiang Y. Lv H. Shen F. Fan L. Zhang H. Huang Y. et al (2024). Strategies in product engineering of mesenchymal stem cell-derived exosomes: unveiling the mechanisms underpinning the promotive effects of mesenchymal stem cell-derived exosomes. Front. Bioeng. Biotechnol.12, 1363780. 10.3389/fbioe.2024.1363780

  • CrossRef
  • Google Scholar

• 109

  Jin Z. Zhan Y. Zheng L. Wei Q. Xu S. Qin Z. (2023). Cannabidiol‐loaded poly lactic‐Co‐glycolic acid nanoparticles with improved bioavailability as a potential for osteoarthritis therapeutic. ChemBioChem24, e202200698. 10.1002/cbic.202200698

  • CrossRef
  • Google Scholar

• 110

  Jung J. H. Kim S. E. Kim H. J. Park K. Song G. G. Choi S. J. (2020). A comparative pilot study of oral diacerein and locally treated diacerein-loaded nanoparticles in a model of osteoarthritis. Int. J. Pharm.581, 119249. 10.1016/j.ijpharm.2020.119249

  • CrossRef
  • Google Scholar

• 111

  Kalashnikova I. Chung S. J. Nafiujjaman M. Hill M. L. Siziba M. E. Contag C. H. et al (2020). Ceria-based nanotheranostic agent for rheumatoid arthritis. Theranostics10, 11863–11880. 10.7150/thno.49069

  • CrossRef
  • Google Scholar

• 112

  Kang C. Jung E. Hyeon H. Seon S. Lee D. (2020). Acid-activatable polymeric curcumin nanoparticles as therapeutic agents for osteoarthritis. Nanomedicine Nanotechnol. Biol. Med.23, 102104. 10.1016/j.nano.2019.102104

  • CrossRef
  • Google Scholar

• 113

  Katz J. N. Arant K. R. Loeser R. F. (2021). Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA325, 568–578. 10.1001/jama.2020.22171

  • CrossRef
  • Google Scholar

• 114

  Knights A. J. Redding S. J. Maerz T. (2023). Inflammation in osteoarthritis: the latest progress and ongoing challenges. Curr. Opin. Rheumatol.35, 128–134. 10.1097/BOR.0000000000000923

  • CrossRef
  • Google Scholar

• 115

  Krishnan Y. Grodzinsky A. J. (2018). Cartilage diseases. Matrix Biol.71–72, 51–69. 10.1016/j.matbio.2018.05.005

  • CrossRef
  • Google Scholar

• 116

  Kuang L. Wu J. Su N. Qi H. Chen H. Zhou S. et al (2020). FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice. Ann. Rheum. Dis.79, 112–122. 10.1136/annrheumdis-2019-215696

  • CrossRef
  • Google Scholar

• 117

  Kuang S. Liu L. Hu Z. Luo M. Fu X. Lin C. et al (2023). A review focusing on the benefits of plant-derived polysaccharides for osteoarthritis. Int. J. Biol. Macromol.228, 582–593. 10.1016/j.ijbiomac.2022.12.153

  • CrossRef
  • Google Scholar

• 118

  Kumar M. A. Baba S. K. Sadida H. Q. Marzooqi S. A. Jerobin J. Altemani F. H. et al (2024). Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct. Target. Ther.9, 27. 10.1038/s41392-024-01735-1

  • CrossRef
  • Google Scholar

• 119

  Kumar S. Adjei I. M. Brown S. B. Liseth O. Sharma B. (2019). Manganese dioxide nanoparticles protect cartilage from inflammation-induced oxidative stress. Biomaterials224, 119467. 10.1016/j.biomaterials.2019.119467

  • CrossRef
  • Google Scholar

• 120

  Kumari A. Kaur A. Aggarwal G. (2023). The emerging potential of siRNA nanotherapeutics in treatment of arthritis. Asian J. Pharm. Sci.18, 100845. 10.1016/j.ajps.2023.100845

  • CrossRef
  • Google Scholar

• 121

  Kus-Liśkiewicz M. Fickers P. Ben Tahar I. (2021). Biocompatibility and cytotoxicity of gold nanoparticles: recent advances in methodologies and regulations. Int. J. Mol. Sci.22, 10952. 10.3390/ijms222010952

  • CrossRef
  • Google Scholar

• 122

  Lambert C. Zappia J. Sanchez C. Florin A. Dubuc J. E. Henrotin Y. (2021). The damage-associated molecular patterns (DAMPs) as potential targets to treat osteoarthritis: perspectives from a review of the literature. Front. Med.7, 607186. 10.3389/fmed.2020.607186

  • CrossRef
  • Google Scholar

• 123

  Lan Q. Lu R. Chen H. Pang Y. Xiong F. Shen C. et al (2020). MMP-13 enzyme and pH responsive theranostic nanoplatform for osteoarthritis. J. Nanobiotechnology18, 117. 10.1186/s12951-020-00666-7

  • CrossRef
  • Google Scholar

• 124

  Lee M.-K. (2020). Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo evidence and recent approaches. Pharmaceutics12, 264. 10.3390/pharmaceutics12030264

  • CrossRef
  • Google Scholar

• 125

  Legré-Boyer V. (2015). Viscosupplementation: techniques, indications, results. Orthop. Traumatol. Surg. Res.101, S101–S108. 10.1016/j.otsr.2014.07.027

  • CrossRef
  • Google Scholar

• 126

  Li D. Wu M. (2021). Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther.6, 291. 10.1038/s41392-021-00687-0

  • CrossRef
  • Google Scholar

• 127

  Li H. Luo Y. Xu Y. Yang L. Hu C. Chen Q. et al (2018). Meloxicam improves cognitive impairment of diabetic rats through COX2-PGE2-EPs-cAMP/pPKA pathway. Mol. Pharm.15, 4121–4131. 10.1021/acs.molpharmaceut.8b00532

  • CrossRef
  • Google Scholar

• 128

  Li L. Wang F. Zhu D. Hu S. Cheng K. Li Z. (2024d). Engineering exosomes and exosome-like nanovesicles for improving tissue targeting and retention. Fundam. Res.S2667325824001481. 10.1016/j.fmre.2024.03.025

  • CrossRef
  • Google Scholar

• 129

  Li R. Hou X. Li L. Guo J. Jiang W. Shang W. (2022b). Application of metal-based nanozymes in inflammatory disease: a review. Front. Bioeng. Biotechnol.10, 920213. 10.3389/fbioe.2022.920213

  • CrossRef
  • Google Scholar

• 130

  Li S. Xiong Y. Zhu H. Ma T. Sun X. Xiao J. et al (2024c). Microenvironment-responsive nanosystems for osteoarthritis therapy. Eng. Regen.5, 92–110. 10.1016/j.engreg.2023.12.002

  • CrossRef
  • Google Scholar

• 131

  Li T. Peng J. Li Q. Shu Y. Zhu P. Hao L. (2022a). The mechanism and role of ADAMTS protein family in osteoarthritis. Biomolecules12, 959. 10.3390/biom12070959

  • CrossRef
  • Google Scholar

• 132

  Li W. Wang Y. Tang Y. Lu H. Qi Y. Li G. et al (2021c). Quercetin alleviates osteoarthritis progression in rats by suppressing inflammation and apoptosis via inhibition of IRAK1/NLRP3 signaling. J. Inflamm. Res.14, 3393–3403. 10.2147/JIR.S311924

  • CrossRef
  • Google Scholar

• 133

  Li X. Dai B. Guo J. Zheng L. Guo Q. Peng J. et al (2021a). Nanoparticle–cartilage interaction: pathology-based intra-articular drug delivery for osteoarthritis therapy. Nano-Micro Lett.13, 149. 10.1007/s40820-021-00670-y

  • CrossRef
  • Google Scholar

• 134

  Li X. Ren Y. Chang K. Wu W. Griffiths H. R. Lu S. et al (2023). Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Front. Immunol.14, 1153915. 10.3389/fimmu.2023.1153915

  • CrossRef
  • Google Scholar

• 135

  Li Y. Xia X. Niu Z. Wang K. Liu J. Li X. (2024a). hCeO2@ Cu5.4O nanoparticle alleviates inflammatory responses by regulating the CTSB–NLRP3 signaling pathway. Front. Immunol.15, 1344098. 10.3389/fimmu.2024.1344098

  • CrossRef
  • Google Scholar

• 136

  Li Y. Yang Y. Qing Y. Li R. Tang X. Guo D. et al (2020). Enhancing ZnO-NP antibacterial and osteogenesis properties in orthopedic applications: a review. Int. J. Nanomedicine15, 6247–6262. 10.2147/IJN.S262876

  • CrossRef
  • Google Scholar

• 137

  Li Y. Zhao J. Guo S. He D. (2024b). siRNA therapy in osteoarthritis: targeting cellular pathways for advanced treatment approaches. Front. Immunol.15, 1382689. 10.3389/fimmu.2024.1382689

  • CrossRef
  • Google Scholar

• 138

  Li Y.-J. Wu J. Y. Liu J. Xu W. Qiu X. Huang S. et al (2021d). Artificial exosomes for translational nanomedicine. J. Nanobiotechnology19, 242. 10.1186/s12951-021-00986-2

  • CrossRef
  • Google Scholar

• 139

  Li Z. Wang J. Ma Y. (2021b). Montelukast attenuates interleukin IL-1β-induced oxidative stress and apoptosis in chondrocytes by inhibiting CYSLTR1 (Cysteinyl Leukotriene Receptor 1) and activating KLF2 (Kruppel like Factor 2). Bioengineered12, 8476–8484. 10.1080/21655979.2021.1984003

  • CrossRef
  • Google Scholar

• 140

  Liang J. Liu P. Yang X. Liu L. Zhang Y. Wang Q. et al (2023). Biomaterial-based scaffolds in promotion of cartilage regeneration: recent advances and emerging applications. J. Orthop. Transl.41, 54–62. 10.1016/j.jot.2023.08.006

  • CrossRef
  • Google Scholar

• 141

  Liao C.-R. Wang S. N. Zhu S. Y. Wang Y. Q. Li Z. Z. Liu Z. Y. et al (2020). Advanced oxidation protein products increase TNF-α and IL-1β expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression. Redox Biol.28, 101306. 10.1016/j.redox.2019.101306

  • CrossRef
  • Google Scholar

• 142

  Lin F. Li Y. Cui W. (2023). Injectable hydrogel microspheres in cartilage repair. Biomed. Technol.1, 18–29. 10.1016/j.bmt.2022.11.002

  • CrossRef
  • Google Scholar

• 143

  Ling H. Zeng Q. Ge Q. Chen J. Yuan W. Xu R. et al (2021). Osteoking decelerates cartilage degeneration in DMM-induced osteoarthritic mice model through TGF-β/smad-dependent manner. Front. Pharmacol.12, 678810. 10.3389/fphar.2021.678810

  • CrossRef
  • Google Scholar

• 144

  Liu L. Tang H. Wang Y. (2023a). Polymeric biomaterials: advanced drug delivery systems in osteoarthritis treatment. Heliyon9, e21544. 10.1016/j.heliyon.2023.e21544

  • CrossRef
  • Google Scholar

• 145

  Liu L. Tang H. Wang Y. (2023b). Nanotechnology-boosted biomaterials for osteoarthritis treatment: current status and future perspectives. Int. J. Nanomedicine18, 4969–4983. 10.2147/IJN.S423737

  • CrossRef
  • Google Scholar

• 146

  Liu P. Chen G. Zhang J. (2022b). A review of liposomes as a drug delivery system: current status of approved products, regulatory environments, and future perspectives. Molecules27, 1372. 10.3390/molecules27041372

  • CrossRef
  • Google Scholar

• 147

  Liu S. Deng Z. Chen K. Jian S. Zhou F. Yang Y. et al (2022a). Cartilage tissue engineering: from proinflammatory and anti-inflammatory cytokines to osteoarthritis treatments (Review). Mol. Med. Rep.25, 99. 10.3892/mmr.2022.12615

  • CrossRef
  • Google Scholar

• 148

  Liu S. Gao X. Wang Y. Wang J. Qi X. Dong K. et al (2022c). Baicalein-loaded silk fibroin peptide nanofibers protect against cisplatin-induced acute kidney injury: fabrication, characterization and mechanism. Int. J. Pharm.626, 122161. 10.1016/j.ijpharm.2022.122161

  • CrossRef
  • Google Scholar

• 149

  Lopez-Miranda J. L. Molina G. A. González-Reyna M. A. España-Sánchez B. L. Esparza R. Silva R. et al (2023). Antibacterial and anti-inflammatory properties of ZnO nanoparticles synthesized by a green method using sargassum extracts. Int. J. Mol. Sci.24, 1474. 10.3390/ijms24021474

  • CrossRef
  • Google Scholar

• 150

  Lowin T. Tingting R. Zurmahr J. Classen T. Schneider M. Pongratz G. (2020). Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts. Cell Death Dis.11, 714. 10.1038/s41419-020-02892-1

  • CrossRef
  • Google Scholar

• 151

  Lu H. Wei J. Liu K. Li Z. Xu T. Yang D. et al (2023b). Radical-scavenging and subchondral bone-regenerating nanomedicine for osteoarthritis treatment. ACS Nano17, 6131–6146. 10.1021/acsnano.3c01789

  • CrossRef
  • Google Scholar

• 152

  Lu R. Wang Y. G. Qu Y. Wang S. X. Peng C. You H. et al (2023a). Dihydrocaffeic acid improves IL-1β-induced inflammation and cartilage degradation via inhibiting NF-κB and MAPK signalling pathways. Bone Jt. Res.12, 259–273. 10.1302/2046-3758.124.BJR-2022-0384.R1

  • CrossRef
  • Google Scholar

• 153

  Luo J. Zhang Y. Zhu S. Tong Y. Ji L. Zhang W. et al (2021). The application prospect of metal/metal oxide nanoparticles in the treatment of osteoarthritis. Naunyn. Schmiedeb. Arch. Pharmacol.394, 1991–2002. 10.1007/s00210-021-02131-0

  • CrossRef
  • Google Scholar

• 154

  Ma Q. (2023). Pharmacological inhibition of the NLRP3 inflammasome: structure, molecular activation, and inhibitor-NLRP3 interaction. Pharmacol. Rev.75, 487–520. 10.1124/pharmrev.122.000629

  • CrossRef
  • Google Scholar

• 155

  Ma Z. Wang Y. Piao T. Liu J. (2016). echinocytic acid inhibits IL-1β-induced COX-2 and iNOS expression in human osteoarthritis chondrocytes. Inflammation39, 543–549. 10.1007/s10753-015-0278-y

  • CrossRef
  • Google Scholar

• 156

  Magni A. Agostoni P. Bonezzi C. Massazza G. Menè P. Savarino V. et al (2021). Management of osteoarthritis: expert opinion on NSAIDs. Pain Ther.10, 783–808. 10.1007/s40122-021-00260-1

  • CrossRef
  • Google Scholar

• 157

  Mancini G. Gonçalves L. M. D. Marto J. Carvalho F. A. Simões S. Ribeiro H. M. et al (2021). Increased therapeutic efficacy of SLN containing etofenamate and ibuprofen in topical treatment of inflammation. Pharmaceutics13, 328. 10.3390/pharmaceutics13030328

  • CrossRef
  • Google Scholar

• 158

  Marinho A. Nunes C. Reis S. (2021). Hyaluronic acid: a key ingredient in the therapy of inflammation. Biomolecules11, 1518. 10.3390/biom11101518

  • CrossRef
  • Google Scholar

• 159

  Maślanka T. Jaroszewski J. J. (2013). In vitro effects of meloxicam on the number, Foxp3 expression, production of selected cytokines, and apoptosis of bovine CD25+CD4+ and CD25-CD4+ cells. J. Vet. Sci.14, 125–134. 10.4142/jvs.2013.14.2.125

  • CrossRef
  • Google Scholar

• 160

  McCulloch K. Litherland G. J. Rai T. S. (2017). Cellular senescence in osteoarthritis pathology. Aging Cell16, 210–218. 10.1111/acel.12562

  • CrossRef
  • Google Scholar

• 161

  McGuckin M. B. Wang J. Ghanma R. Qin N. Palma S. D. Donnelly R. F. et al (2022). Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes. J. Control. Release345, 334–353. 10.1016/j.jconrel.2022.03.012

  • CrossRef
  • Google Scholar

• 162

  Mirza E. H. Pan‐Pan C. Wan Ibrahim W. M. A. B. Djordjevic I. Pingguan‐Murphy B. (2015). Chondroprotective effect of zinc oxide nanoparticles in conjunction with hypoxia on bovine cartilage‐matrix synthesis. J. Biomed. Mater. Res. A103, 3554–3563. 10.1002/jbm.a.35495

  • CrossRef
  • Google Scholar

• 163

  Mitchell M. J. Billingsley M. M. Haley R. M. Wechsler M. E. Peppas N. A. Langer R. (2021). Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov.20, 101–124. 10.1038/s41573-020-0090-8

  • CrossRef
  • Google Scholar

• 164

  Mizuno M. Matsuzaki T. Ozeki N. Katano H. Koga H. Takebe T. et al (2022). Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs. Stem Cell Res. Ther.13, 177. 10.1186/s13287-022-02850-y

  • CrossRef
  • Google Scholar

• 165

  Molnar V. Matišić V. Kodvanj I. Bjelica R. Jeleč Ž. Hudetz D. et al (2021). Cytokines and chemokines involved in osteoarthritis pathogenesis. Int. J. Mol. Sci.22, 9208. 10.3390/ijms22179208

  • CrossRef
  • Google Scholar

• 166

  Moon S.-M. Lee S. A. Han S. H. Park B. R. Choi M. S. Kim J. S. et al (2018). Aqueous extract of Codium fragile alleviates osteoarthritis through the MAPK/NF-κB pathways in IL-1β-induced rat primary chondrocytes and a rat osteoarthritis model. Biomed. Pharmacother.97, 264–270. 10.1016/j.biopha.2017.10.130

  • CrossRef
  • Google Scholar

• 167

  Mu P. Feng J. Hu Y. Xiong F. Ma X. Tian L. (2022). Botanical drug extracts combined with biomaterial carriers for osteoarthritis cartilage degeneration treatment: a review of 10 Years of research. Front. Pharmacol.12, 789311. 10.3389/fphar.2021.789311

  • CrossRef
  • Google Scholar

• 168

  Munir A. Muhammad F. Zaheer Y. Ali M. A. Iqbal M. Rehman M. et al (2021). Synthesis of naringenin loaded lipid based nanocarriers and their in-vivo therapeutic potential in a rheumatoid arthritis model. J. Drug Deliv. Sci. Technol.66, 102854. 10.1016/j.jddst.2021.102854

  • CrossRef
  • Google Scholar

• 169

  Nagy E. Vajda E. Vari C. Sipka S. Fárr A. M. Horváth E. (2017). Meloxicam ameliorates the cartilage and subchondral bone deterioration in monoiodoacetate-induced rat osteoarthritis. PeerJ5, e3185. 10.7717/peerj.3185

  • CrossRef
  • Google Scholar

• 170

  Nandhini J. Karthikeyan E. Elizabeth Rani E. Karthikha V. Sakthi Sanjana D. Jeevitha H. et al (2024). Advancing engineered approaches for sustainable wound regeneration and repair: harnessing the potential of green synthesized silver nanoparticles. Eng. Regen.5, 306–325. 10.1016/j.engreg.2024.06.004

  • CrossRef
  • Google Scholar

• 171

  Nayal R. Mejjo D. Abajy M. Y. (2024). Anti inflammatory properties and safety of green synthesized metal and metal oxide nanoparticles: a review article. Eur. J. Med. Chem. Rep.11, 100169. 10.1016/j.ejmcr.2024.100169

  • CrossRef
  • Google Scholar

• 172

  Nelson A. E. Renner J. B. Schwartz T. A. Kraus V. B. Helmick C. G. Jordan J. M. (2011). Differences in multijoint radiographic osteoarthritis phenotypes among african Americans and caucasians: the johnston county osteoarthritis Project. Arthritis Rheum.63, 3843–3852. 10.1002/art.30610

  • CrossRef
  • Google Scholar

• 173

  Nunes R. D. M. Girão V. C. C. Cunha P. L. R. Feitosa J. P. A. Pinto A. C. M. D. Rocha F. A. C. (2021). Decreased sulfate content and zeta potential distinguish glycosaminoglycans of the extracellular matrix of osteoarthritis cartilage. Front. Med.8, 612370. 10.3389/fmed.2021.612370

  • CrossRef
  • Google Scholar

• 174

  Oo W. M. Little C. Duong V. Hunter D. J. (2021). The development of disease-modifying therapies for osteoarthritis (DMOADs): the evidence to date. Drug Des. devel. Ther.15, 2921–2945. 10.2147/DDDT.S295224

  • CrossRef
  • Google Scholar

• 175

  Pandey S. Shaikh F. Gupta A. Tripathi P. Yadav J. S. (2021). A recent update: solid lipid nanoparticles for effective drug delivery. Adv. Pharm. Bull.1, 17–33. 10.34172/apb.2022.007

  • CrossRef
  • Google Scholar

• 176

  Pangli H. Vatanpour S. Hortamani S. Jalili R. Ghahary A. (2021). Incorporation of silver nanoparticles in hydrogel matrices for controlling wound infection. J. Burn Care Res.42, 785–793. 10.1093/jbcr/iraa205

  • CrossRef
  • Google Scholar

• 177

  Panova E. Jones G. (2015). Benefit–risk assessment of diacerein in the treatment of osteoarthritis. Drug Saf.38, 245–252. 10.1007/s40264-015-0266-z

  • CrossRef
  • Google Scholar

• 178

  Park H. Lee H. R. Shin H. J. Park J. A. Joo Y. Kim S. M. et al (2022). p16INK4a-siRNA nanoparticles attenuate cartilage degeneration in osteoarthritis by inhibiting inflammation in fibroblast-like synoviocytes. Biomater. Sci.10, 3223–3235. 10.1039/d1bm01941d

  • CrossRef
  • Google Scholar

• 179

  Peng Y. Qu R. Xu S. Bi H. Guo D. (2024). Regulatory mechanism and therapeutic potentials of naringin against inflammatory disorders. Heliyon10, e24619. 10.1016/j.heliyon.2024.e24619

  • CrossRef
  • Google Scholar

• 180

  Pontes A. P. Welting T. J. M. Rip J. Creemers L. B. (2022). Polymeric nanoparticles for drug delivery in osteoarthritis. Pharmaceutics14, 2639. 10.3390/pharmaceutics14122639

  • CrossRef
  • Google Scholar

• 181

  Pourmadadi M. Rahmani E. Shamsabadipour A. Mahtabian S. Ahmadi M. Rahdar A. et al (2022). Role of iron oxide (Fe2O3) nanocomposites in advanced biomedical applications: a state-of-the-art review. Nanomaterials12, 3873. 10.3390/nano12213873

  • CrossRef
  • Google Scholar

• 182

  Qiao K. Xu L. Tang J. Wang Q. Lim K. S. Hooper G. et al (2022). The advances in nanomedicine for bone and cartilage repair. J. Nanobiotechnology20, 141. 10.1186/s12951-022-01342-8

  • CrossRef
  • Google Scholar

• 183

  Qin S. Zhu J. Zhang G. Sui Q. Niu Y. Ye W. et al (2023). Research progress of functional motifs based on growth factors in cartilage tissue engineering: a review. Front. Bioeng. Biotechnol.11, 1127949. 10.3389/fbioe.2023.1127949

  • CrossRef
  • Google Scholar

• 184

  Qiu L.-Y. Yan L. Zhang L. Jin Y.-M. Zhao Q.-H. (2013). Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery. Int. J. Pharm.456, 315–324. 10.1016/j.ijpharm.2013.08.071

  • CrossRef
  • Google Scholar

• 185

  Quero L. Tiaden A. N. Hanser E. Roux J. Laski A. Hall J. et al (2020). miR-221-3p drives the shift of M2-macrophages to a pro-inflammatory function by suppressing JAK3/STAT3 activation. Front. Immunol.10, 3087. 10.3389/fimmu.2019.03087

  • CrossRef
  • Google Scholar

• 186

  Raghu H. Lepus C. M. Wang Q. Wong H. H. Lingampalli N. Oliviero F. et al (2017). CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Ann. Rheum. Dis.76, 914–922. 10.1136/annrheumdis-2016-210426

  • CrossRef
  • Google Scholar

• 187

  Rahmati M. Mobasheri A. Mozafari M. (2016). Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone85, 81–90. 10.1016/j.bone.2016.01.019

  • CrossRef
  • Google Scholar

• 188

  Rai M. F. Pan H. Yan H. Sandell L. J. Pham C. T. N. Wickline S. A. (2019). Applications of RNA interference in the treatment of arthritis. Transl. Res.214, 1–16. 10.1016/j.trsl.2019.07.002

  • CrossRef
  • Google Scholar

• 189

  Ramirez-Perez S. Reyes-Perez I. V. Martinez-Fernandez D. E. Hernandez-Palma L. A. Bhattaram P. (2022). Targeting inflammasome-dependent mechanisms as an emerging pharmacological approach for osteoarthritis therapy. iScience25, 105548. 10.1016/j.isci.2022.105548

  • CrossRef
  • Google Scholar

• 190

  Rao C. Shi S. (2022). Development of nanomaterials to target articular cartilage for osteoarthritis therapy. Front. Mol. Biosci.9, 900344. 10.3389/fmolb.2022.900344

  • CrossRef
  • Google Scholar

• 191

  Ravetti S. Garro A. G. Gaitán A. Murature M. Galiano M. Brignone S. G. et al (2023). Naringin: nanotechnological strategies for potential pharmaceutical applications. Pharmaceutics15, 863. 10.3390/pharmaceutics15030863

  • CrossRef
  • Google Scholar

• 192

  Ren G. Al-Jezani N. Railton P. Powell J. N. Krawetz R. J. (2021). CCL22 induces pro-inflammatory changes in fibroblast-like synoviocytes. iScience24, 101943. 10.1016/j.isci.2020.101943

  • CrossRef
  • Google Scholar

• 193

  Roelofs A. J. Kania K. Rafipay A. J. Sambale M. Kuwahara S. T. Collins F. L. et al (2020). Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis. Ann. Rheum. Dis.79, 1625–1634. 10.1136/annrheumdis-2020-218350

  • CrossRef
  • Google Scholar

• 194

  Roseti L. Desando G. Cavallo C. Petretta M. Grigolo B. (2019). Articular cartilage regeneration in osteoarthritis. Cells8, 1305. 10.3390/cells8111305

  • CrossRef
  • Google Scholar

• 195

  Sadalage P. S. Patil R. V. Havaldar D. V. Gavade S. S. Santos A. C. Pawar K. D. (2021). Optimally biosynthesized, PEGylated gold nanoparticles functionalized with quercetin and camptothecin enhance potential anti-inflammatory, anti-cancer and anti-angiogenic activities. J. Nanobiotechnology19, 84. 10.1186/s12951-021-00836-1

  • CrossRef
  • Google Scholar

• 196

  Said S. S. Campbell S. Hoare T. (2019). Externally addressable smart drug delivery vehicles: current technologies and future directions. Chem. Mater.31, 4971–4989. 10.1021/acs.chemmater.9b01798

  • CrossRef
  • Google Scholar

• 197

  Salathia S. Gigliobianco M. R. Casadidio C. Di Martino P. Censi R. (2023). Hyaluronic acid-based nanosystems for CD44 mediated anti-inflammatory and antinociceptive activity. Int. J. Mol. Sci.24, 7286. 10.3390/ijms24087286

  • CrossRef
  • Google Scholar

• 198

  Salehi B. Stojanović-Radić Z. Matejić J. Sharifi-Rad M. Anil Kumar N. V. Martins N. et al (2019). The therapeutic potential of curcumin: a review of clinical trials. Eur. J. Med. Chem.163, 527–545. 10.1016/j.ejmech.2018.12.016

  • CrossRef
  • Google Scholar

• 199

  Sanità G. Carrese B. Lamberti A. (2020). Nanoparticle surface functionalization: how to improve biocompatibility and cellular internalization. Front. Mol. Biosci.7, 587012. 10.3389/fmolb.2020.587012

  • CrossRef
  • Google Scholar

• 200

  Sarabia-Vallejo Á. Caja M. D. M. Olives A. I. Martín M. A. Menéndez J. C. (2023). Cyclodextrin inclusion complexes for improved drug bioavailability and activity: synthetic and analytical aspects. Pharmaceutics15, 2345. 10.3390/pharmaceutics15092345

  • CrossRef
  • Google Scholar

• 201

  Scanzello C. R. Goldring S. R. (2012). The role of synovitis in osteoarthritis pathogenesis. Bone51, 249–257. 10.1016/j.bone.2012.02.012

  • CrossRef
  • Google Scholar

• 202

  Seo B.-B. Kwon Y. Kim J. Hong K. H. Kim S. E. Song H. R. et al (2022). Injectable polymeric nanoparticle hydrogel system for long-term anti-inflammatory effect to treat osteoarthritis. Bioact. Mater.7, 14–25. 10.1016/j.bioactmat.2021.05.028

  • CrossRef
  • Google Scholar

• 203

  Serra M. Casas A. Toubarro D. Barros A. N. Teixeira J. A. (2023). Microbial hyaluronic acid production: a review. Molecules28, 2084. 10.3390/molecules28052084

  • CrossRef
  • Google Scholar

• 204

  Shi F. Wei Z. Zhao Y. Xu X. (2016). Nanostructured lipid carriers loaded with baicalin: an efficient carrier for enhanced antidiabetic effects. Pharmacogn. Mag.12, 198–202. 10.4103/0973-1296.186347

  • CrossRef
  • Google Scholar

• 205

  Shin H. J. Park H. Shin N. Kwon H. H. Yin Y. Hwang J. A. et al (2020a). p47phox siRNA-loaded PLGA nanoparticles suppress ROS/oxidative stress-induced chondrocyte damage in osteoarthritis. Polymers12, 443. 10.3390/polym12020443

  • CrossRef
  • Google Scholar

• 206

  Shin H. J. Park H. Shin N. Shin J. Gwon D. H. Kwon H. H. et al (2020b). p66shc siRNA nanoparticles ameliorate chondrocytic mitochondrial dysfunction in osteoarthritis. Int. J. Nanomedicine15, 2379–2390. 10.2147/IJN.S234198

  • CrossRef
  • Google Scholar

• 207

  Shin M.-R. Kim H. Y. Choi H. Y. Park K. S. Choi H. J. Roh S. S. (2022). Boswellia serrata extract, 5-loxin®, prevents joint pain and cartilage degeneration in a rat model of osteoarthritis through inhibition of inflammatory responses and restoration of matrix homeostasis. Evid. Based Complement. Altern. Med.2022, 1–11. 10.1155/2022/3067526

  • CrossRef
  • Google Scholar

• 208

  Singh A. P. Biswas A. Shukla A. Maiti P. (2019). Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles. Signal Transduct. Target. Ther.4, 33. 10.1038/s41392-019-0068-3

  • CrossRef
  • Google Scholar

• 209

  Skou S. T. Roos E. M. Laursen M. B. Rathleff M. S. Arendt-Nielsen L. Simonsen O. et al (2015). A randomized, controlled trial of total knee replacement. N. Engl. J. Med.373, 1597–1606. 10.1056/NEJMoa1505467

  • CrossRef
  • Google Scholar

• 210

  Sohail R. Mathew M. Patel K. K. Reddy S. A. Haider Z. Naria M. et al (2023). Effects of non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective NSAIDs on the gastrointestinal tract: a narrative review. Cureus15, e37080. 10.7759/cureus.37080

  • CrossRef
  • Google Scholar

• 211

  Son K. M. Hong J. I. Kim D. H. Jang D. G. Crema M. D. Kim H. A. (2020). Absence of pain in subjects with advanced radiographic knee osteoarthritis. BMC Musculoskelet. Disord.21, 640. 10.1186/s12891-020-03647-x

  • CrossRef
  • Google Scholar

• 212

  Stiller C. Hjemdahl P. (2022). Lessons from 20 years with COX‐2 inhibitors: importance of dose–response considerations and fair play in comparative trials. J. Intern. Med.292, 557–574. 10.1111/joim.13505

  • CrossRef
  • Google Scholar

• 213

  Strokotova A. V. Grigorieva E. V. (2022). Glucocorticoid effects on proteoglycans and glycosaminoglycans. Int. J. Mol. Sci.23, 15678. 10.3390/ijms232415678

  • CrossRef
  • Google Scholar

• 214

  Tambe A. Pandita N. Kharkar P. Sahu N. (2018). Encapsulation of boswellic acid with β- and hydroxypropyl-β-cyclodextrin: synthesis, characterization, in vitro drug release and molecular modelling studies. J. Mol. Struct.1154, 504–510. 10.1016/j.molstruc.2017.10.061

  • CrossRef
  • Google Scholar

• 215

  Tan F. Li X. Wang Z. Li J. Shahzad K. Zheng J. (2024). Clinical applications of stem cell-derived exosomes. Signal Transduct. Target. Ther.9, 17. 10.1038/s41392-023-01704-0

  • CrossRef
  • Google Scholar

• 216

  Tan F. Wang D. Yuan Z. (2020). The fibroblast-like synoviocyte derived exosomal long non-coding RNA H19 alleviates osteoarthritis progression through the miR-106b-5p/TIMP2 Axis. Inflammation43, 1498–1509. 10.1007/s10753-020-01227-8

  • CrossRef
  • Google Scholar

• 217

  Tao S.-C. Yuan T. Zhang Y. L. Yin W. J. Guo S. C. Zhang C. Q. (2017). Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics7, 180–195. 10.7150/thno.17133

  • CrossRef
  • Google Scholar

• 218

  Teixeira S. Carvalho M. A. Castanheira E. M. S. (2022). Functionalized liposome and albumin-based systems as carriers for poorly water-soluble anticancer drugs: an updated review. Biomedicines10, 486. 10.3390/biomedicines10020486

  • CrossRef
  • Google Scholar

• 219

  Tenchov R. Sasso J. M. Wang X. Liaw W. S. Chen C. A. Zhou Q. A. (2022). Exosomes─Nature’s lipid nanoparticles, a rising star in drug delivery and diagnostics. ACS Nano16, 17802–17846. 10.1021/acsnano.2c08774

  • CrossRef
  • Google Scholar

• 220

  Teng L. Shen Y. Qu Y. Yang L. Yang Y. Jian X. et al (2023). Cyasterone inhibits IL-1β-mediated apoptosis and inflammation via the NF-κB and MAPK signaling pathways in rat chondrocytes and ameliorates osteoarthritis vivo. Chin. J. Nat. Med.21, 99–112. 10.1016/S1875-5364(23)60388-7

  • CrossRef
  • Google Scholar

• 221

  Testa G. Giardina S. M. C. Culmone A. Vescio A. Turchetta M. Cannavò S. et al (2021). Intra-articular injections in knee osteoarthritis: a review of literature. J. Funct. Morphol. Kinesiol.6, 15. 10.3390/jfmk6010015

  • CrossRef
  • Google Scholar

• 222

  Thielen N. Van Der Kraan P. Van Caam A. (2019). TGFβ/BMP signaling pathway in cartilage homeostasis. Cells8, 969. 10.3390/cells8090969

  • CrossRef
  • Google Scholar

• 223

  Tian Y. Gou J. Zhang H. Lu J. Jin Z. Jia S. et al (2021). The anti-inflammatory effects of 15-HETE on osteoarthritis during treadmill exercise. Life Sci.273, 119260. 10.1016/j.lfs.2021.119260

  • CrossRef
  • Google Scholar

• 224

  Ting Y. Jiang Y. Zhao S. Nibber T. Huang Q. (2018). Self-nanoemulsifying system (SNES) enhanced oral bioavailability of boswellic acids. J. Funct. Foods40, 520–526. 10.1016/j.jff.2017.11.043

  • CrossRef
  • Google Scholar

• 225

  Togo K. Ebata N. Yonemoto N. Abraham L. (2022). Safety risk associated with use of nonsteroidal anti‐inflammatory drugs in Japanese elderly compared with younger patients with osteoarthritis and/or chronic low back pain: a retrospective database study. Pain Pract.22, 200–209. 10.1111/papr.13079

  • CrossRef
  • Google Scholar

• 226

  Tsujii A. Ohori T. Hanai H. Nakamura N. (2024). Next generation approaches for cartilage repair and joint preservation. J. Cartil. Jt. Preserv.4, 100177. 10.1016/j.jcjp.2024.100177

  • CrossRef
  • Google Scholar

• 227

  Van Osch G. J. V. M. Brittberg M. Dennis J. E. Bastiaansen-Jenniskens Y. M. Erben R. G. Konttinen Y. T. et al (2009). Cartilage repair: past and future – lessons for regenerative medicine. J. Cell. Mol. Med.13, 792–810. 10.1111/j.1582-4934.2009.00789.x

  • CrossRef
  • Google Scholar

• 228

  Vučković S. Srebro D. Vujović K. S. Vučetić Č. Prostran M. (2018). Cannabinoids and pain: new insights from old molecules. Front. Pharmacol.9, 1259. 10.3389/fphar.2018.01259

  • CrossRef
  • Google Scholar

• 229

  Wang L. Xu B. Li S. (2022b). Quercetin activates autophagy suppresses apoptosis, inflammation and cartilage matrix degradation in LPS-induced chondrocytes through targeting AMPK/mTOR/ULK1 signaling pathway. Prepr. A. T. 10.21203/rs.3.rs-1541634/v1

  • CrossRef
  • Google Scholar

• 230

  Wang M. Wu Y. Li G. Lin Q. Zhang W. Liu H. et al (2024). Articular cartilage repair biomaterials: strategies and applications. Mater. Today Bio24, 100948. 10.1016/j.mtbio.2024.100948

  • CrossRef
  • Google Scholar

• 231

  Wang X. Zhao X. Zhong Y. Shen J. An W. (2022d). Biomimetic exosomes: a new generation of drug delivery system. Front. Bioeng. Biotechnol.10, 865682. 10.3389/fbioe.2022.865682

  • CrossRef
  • Google Scholar

• 232

  Wang Y. Liu L. Le Z. Tay A. (2022a). Analysis of nanomedicine efficacy for osteoarthritis. Adv. NanoBiomed Res.2, 2200085. 10.1002/anbr.202200085

  • CrossRef
  • Google Scholar

• 233

  Wang Z.-Z. Jia Y. Wang G. He H. Cao L. Shi Y. et al (2022c). Dynamic covalent hydrogel of natural product baicalin with antibacterial activities. RSC Adv.12, 8737–8742. 10.1039/d1ra07553e

  • CrossRef
  • Google Scholar

• 234

  Wen J. Li H. Dai H. Hua S. Long X. Li H. et al (2023). Intra-articular nanoparticles based therapies for osteoarthritis and rheumatoid arthritis management. Mater. Today Bio19, 100597. 10.1016/j.mtbio.2023.100597

  • CrossRef
  • Google Scholar

• 235

  Wojdasiewicz P. Poniatowski Ł. A. Szukiewicz D. (2014). The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm.2014, 1–19. 10.1155/2014/561459

  • CrossRef
  • Google Scholar

• 236

  Wu M. Wu S. Chen W. Li Y.-P. (2024). The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res.34, 101–123. 10.1038/s41422-023-00918-9

  • CrossRef
  • Google Scholar

• 237

  Xiao Y. Zhang L. (2023). Mechanistic and therapeutic insights into the function of NLRP3 inflammasome in sterile arthritis. Front. Immunol.14, 1273174. 10.3389/fimmu.2023.1273174

  • CrossRef
  • Google Scholar

• 238

  Xiong L. Bao H. Li S. Gu D. Li Y. Yin Q. et al (2023). Cerium oxide nanoparticles protect against chondrocytes and cartilage explants from oxidative stress via Nrf2/HO-1 pathway in temporomandibular joint osteoarthritis. Front. Bioeng. Biotechnol.11, 1076240. 10.3389/fbioe.2023.1076240

  • CrossRef
  • Google Scholar

• 239

  Xiong W. Lan Q. Liang X. Zhao J. Huang H. Zhan Y. et al (2021). Cartilage-targeting poly(ethylene glycol) (PEG)-formononetin (FMN) nanodrug for the treatment of osteoarthritis. J. Nanobiotechnology19, 197. 10.1186/s12951-021-00945-x

  • CrossRef
  • Google Scholar

• 240

  Xu C. Jiang Y. Wang H. Zhang Y. Ye Y. Qin H. et al (2023). Arthritic microenvironment actuated nanomotors for active rheumatoid arthritis therapy. Adv. Sci.10, 2204881. 10.1002/advs.202204881

  • CrossRef
  • Google Scholar

• 241

  Xu F. Zhao L. J. Liao T. Li Z. C. Wang L. L. Lin P. Y. et al (2022). Ononin ameliorates inflammation and cartilage degradation in rat chondrocytes with IL-1β-induced osteoarthritis by downregulating the MAPK and NF-κB pathways. BMC Complement. Med. Ther.22, 25. 10.1186/s12906-022-03504-5

  • CrossRef
  • Google Scholar

• 242

  Yan H. Duan X. Pan H. Akk A. Sandell L. J. Wickline S. A. et al (2019). Development of a peptide-siRNA nanocomplex targeting NF- κB for efficient cartilage delivery. Sci. Rep.9, 442. 10.1038/s41598-018-37018-3

  • CrossRef
  • Google Scholar

• 243

  Yang G. Kang H. C. Cho Y.-Y. Lee H. S. Lee J. Y. (2022). Inflammasomes and their roles in arthritic disease pathogenesis. Front. Mol. Biosci.9, 1027917. 10.3389/fmolb.2022.1027917

  • CrossRef
  • Google Scholar

• 244

  Yao M. Zhang C. Ni L. Ji X. Hong J. Chen Y. et al (2022). Cepharanthine ameliorates chondrocytic inflammation and osteoarthritis via regulating the MAPK/NF-κB-Autophagy pathway. Front. Pharmacol.13, 854239. 10.3389/fphar.2022.854239

  • CrossRef
  • Google Scholar

• 245

  Yetisgin A. A. Cetinel S. Zuvin M. Kosar A. Kutlu O. (2020). Therapeutic nanoparticles and their targeted delivery applications. Molecules25, 2193. 10.3390/molecules25092193

  • CrossRef
  • Google Scholar

• 246

  Yi X. Leng P. Wang S. Liu L. Xie B. (2024). Functional nanomaterials for the treatment of osteoarthritis. Int. J. Nanomedicine19, 6731–6756. 10.2147/IJN.S465243

  • CrossRef
  • Google Scholar

• 247

  Yu B. Tai H. C. Xue W. Lee L. J. Lee R. J. (2010). Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol. Membr. Biol.27, 286–298. 10.3109/09687688.2010.521200

  • CrossRef
  • Google Scholar

• 248

  Zerrillo L. Gigliobianco M. R. D'Atri D. Garcia J. P. Baldazzi F. Ridwan Y. et al (2022). PLGA nanoparticles grafted with hyaluronic acid to improve site-specificity and drug dose delivery in osteoarthritis nanotherapy. Nanomaterials12, 2248. 10.3390/nano12132248

  • CrossRef
  • Google Scholar

• 249

  Zha K. Li X. Yang Z. Tian G. Sun Z. Sui X. et al (2021). Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application. Npj Regen. Med.6, 14. 10.1038/s41536-021-00122-6

  • CrossRef
  • Google Scholar

• 250

  Zhai Q. Chen X. Fei D. Guo X. He X. Zhao W. et al (2022). Nanorepairers rescue inflammation‐induced mitochondrial dysfunction in mesenchymal stem cells. Adv. Sci.9, 2103839. 10.1002/advs.202103839

  • CrossRef
  • Google Scholar

• 251

  Zhang Q. Xiang E. Rao W. Zhang Y. Xiao C. Li C. et al (2021). Intra-articular injection of human umbilical cord mesenchymal stem cells ameliorates monosodium iodoacetate-induced osteoarthritis in rats by inhibiting cartilage degradation and inflammation. Bone Jt. Res.10, 226–236. 10.1302/2046-3758.103.BJR-2020-0206.R2

  • CrossRef
  • Google Scholar

• 252

  Zhang S. Wang J. Pan J. (2016). Baicalin-loaded PEGylated lipid nanoparticles: characterization, pharmacokinetics, and protective effects on acute myocardial ischemia in rats. Drug Deliv.23, 3696–3703. 10.1080/10717544.2016.1223218

  • CrossRef
  • Google Scholar

• 253

  Zhang S. Zhang M. Li X. Li G. Yang B. Lu X. et al (2022b). Nano-based Co-delivery system for treatment of rheumatoid arthritis. Molecules27, 5973. 10.3390/molecules27185973

  • CrossRef
  • Google Scholar

• 254

  Zhang X. You Y. Sun Y. Guo X. Lin H. Zong M. et al (2022c). Catalytic anti-oxidative stress for osteoarthritis treatment by few-layered phosphorene. Mater. Today Bio17, 100462. 10.1016/j.mtbio.2022.100462

  • CrossRef
  • Google Scholar

• 255

  Zhang Z. Dalan R. Hu Z. Wang J. W. Chew N. W. Poh K. K. et al (2022a). Reactive oxygen species scavenging nanomedicine for the treatment of ischemic heart disease. Adv. Mater.34, 2202169. 10.1002/adma.202202169

  • CrossRef
  • Google Scholar

• 256

  Zhao C. Jiang W. Zhou N. Liao J. Yang M. Hu N. et al (2017). Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs). Genes Dis.4, 229–239. 10.1016/j.gendis.2017.10.004

  • CrossRef
  • Google Scholar

• 257

  Zhao G. Zeng Q. Zhang S. Zhong Y. Wang C. Chen Y. et al (2019). Effect of carrier lipophilicity and preparation method on the properties of andrographolide–solid dispersion. Pharmaceutics11, 74. 10.3390/pharmaceutics11020074

  • CrossRef
  • Google Scholar

• 258

  Zhao X. Gu M. Xu X. Wen X. Yang G. Li L. et al (2020). CCL3/CCR1 mediates CD14+CD16− circulating monocyte recruitment in knee osteoarthritis progression. Osteoarthr. Cartil.28, 613–625. 10.1016/j.joca.2020.01.009

  • CrossRef
  • Google Scholar

• 259

  Zheng K. Bai J. Yang H. Xu Y. Pan G. Wang H. et al (2023). Nanomaterial-assisted theranosis of bone diseases. Bioact. Mater.24, 263–312. 10.1016/j.bioactmat.2022.12.014

  • CrossRef
  • Google Scholar

• 260

  Zhou K. Yang C. Shi K. Liu Y. Hu D. He X. et al (2023). Activated macrophage membrane-coated nanoparticles relieve osteoarthritis-induced synovitis and joint damage. Biomaterials295, 122036. 10.1016/j.biomaterials.2023.122036

  • CrossRef
  • Google Scholar

• 261

  Zhou X. Tao Y. Liang C. Zhang Y. Li H. Chen Q. et al (2015). BMP3 alone and together with TGF-β promote the differentiation of human mesenchymal stem cells into a nucleus pulposus-like phenotype. Int. J. Mol. Sci.16 (9), 20344–20359. 10.3390/ijms160920344

  • CrossRef
  • Google Scholar

• 262

  Zhu J. Zhen G. An S. Wang X. Wan M. Li Y. et al (2020). Aberrant subchondral osteoblastic metabolism modifies NaV1.8 for osteoarthritis. eLife9, e57656. 10.7554/eLife.57656

  • CrossRef
  • Google Scholar

• 263

  Zhu X. Chan Y. T. Yung P. S. H. Tuan R. S. Jiang Y. (2021). Subchondral bone remodeling: a therapeutic target for osteoarthritis. Front. Cell Dev. Biol.8, 607764. 10.3389/fcell.2020.607764

  • CrossRef
  • Google Scholar

• 264

  Zhuang C. Sun R. Zhang Y. Zou Q. Zhou J. Dong N. et al (2024). Treatment of rheumatoid arthritis based on the inherent bioactivity of black phosphorus nanosheets. Aging Dis., 0. 10.14336/AD.2024.0319

  • CrossRef
  • Google Scholar

• 265

  Zou J. Yang W. Cui W. Li C. Ma C. Ji X. et al (2023). Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon–bone healing. J. Nanobiotechnology21, 14. 10.1186/s12951-023-01778-6

  • CrossRef
  • Google Scholar

• 266

  Zou Z. Sun M. Yin W. Yang L. Kong L. (2021). Avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation. Phytomedicine91, 153657. 10.1016/j.phymed.2021.153657

  • CrossRef
  • Google Scholar