Polymeric nanoparticles-based targeted delivery of drugs and bioactive compounds for arthritis management

Abstract

This review explores the potential of polymeric nanoparticles (PNPs) as targeted drug delivery systems for arthritic treatment, overcoming the limitations of the present therapy. A thorough literature search was conducted on the databases PubMed, Scopus, and Web of Science to find published articles on the use of polymeric nanoparticles in the treatment of arthritis. This includes synthesis methods, mechanisms in drug delivery, and applications of PNPs. Polymeric nanoparticles showed excellent promise in the management of arthritis through enhanced stability of drugs, controlled and sustained drug release, and reduced systemic side effects. Some of the highlighted biocompatible and targeting capabilities of natural and synthetic polymers include chitosan, hyaluronic acid, and PLGA. Bioactive compounds such as curcumin and resveratrol delivered by PNPs enhanced therapeutic efficacy in preclinical arthritis models. Despite their promise, challenges such as rapid clearance and manufacturing scalability remain critical barriers. Polymeric nanoparticles offer a transformative approach to arthritis management by enabling targeted, sustained, and safe drug delivery. Translation into clinical applications would thus require developments in nanoparticle design, personalized medicine, and scalable production techniques.

Graphical Abstract

PLAIN LANGUAGE SUMMARY

Arthritis is a medical problem affecting millions worldwide, causing joint pain, swelling, and stiffness. Common types are rheumatoid arthritis, osteoarthritis, and gout. Current treatments (NSAIDs, DMARDs) have side effects, like irritation in the stomach and kidney or heart problems. Although lifestyle changes and physical treatment could ease the signs of disease, they are not enough to control the disease alone. This review discusses polymeric nanoparticles (PNPs) as a solution, as these nanoscale carriers deliver drugs directly to the affected joints. They also reduce contact with healthy tissues and reduce side effects. They also protect drugs from breaking down too quickly, allowing for long-lasting release in the body. PNPs can also be functionalized with ligands or coatings to improve target specificity and retention in inflamed joints. For example, PNPs functionalized with hyaluronic acid showed promise in arthritis therapy. Drugs like dexamethasone and methotrexate have shown efficacy when delivered via PNPs. Also, natural compounds, such as resveratrol and curcumin, showed improved therapeutic advantages. So, PNPs offer a revolutionary method for managing arthritis by making drugs more effective, safer, and longer lasting.

ARTICLE HIGHLIGHTS

Introduction

• Arthritis is a widespread health concern impacting millions, with osteoarthritis, rheumatoid arthritis, and gout being the most common types.

• Currently used drugs, such as NSAIDs, DMARDs, and corticosteroids, frequently cause substantial systemic side effects and do not adequately address inflammation in the joints.

Current approaches for the treatment of arthritis

• NSAIDs are commonly used to alleviate pain and inflammation, but they can lead to gastrointestinal, renal, and cardiovascular issues.

• DMARDs and biologics address the root cause of inflammation, though they necessitate ongoing monitoring for potential side effects.

• Corticosteroids offer temporary relief but are not recommended for prolonged use due to the risk of systemic toxicity.

• While lifestyle changes and physical therapy can support pharmacological treatments, they are not adequate for managing severe cases.

Targeted drug delivery for arthritis treatment

• Polymeric nanoparticles enable precise drug delivery to inflamed joints, minimizing systemic exposure and reducing side effects.

• Nanoparticles can improve drug stability, facilitate controlled release, and increase patient adherence to treatment.

• Innovative designs feature stimuli-responsive systems that release drugs in response to environmental changes like pH or temperature.

Literature search and selection of articles

• A literature search was performed using databases, such as PubMed, Scopus, and Web of Science to explore recent developments in polymeric nanoparticles for treating arthritis.

• Articles were chosen for their relevance to nanoparticle-based treatments and their possible clinical applications.

Polymeric nanoparticles as nanoscale carriers: synthesis and structure

• Polymeric nanoparticles are produced through techniques such as emulsion polymerization, nanoprecipitation, and solvent evaporation.

• These nanoparticles can be modified with ligands to improve targeting and optimize drug delivery to inflamed tissues.

• Biocompatible polymers, including PLGA, chitosan, and hyaluronic acid, are frequently used due to their stability and therapeutic advantages.

Polymeric nanoparticles in drug delivery for arthritis treatment

• Nanoparticles enhance the bioavailability and effectiveness of drugs like methotrexate and dexamethasone.

• Functionalized nanoparticles, such as HA-modified carriers, show better targeting and extended retention in inflamed joints.

• Bioactive compounds like curcumin and resveratrol have improved therapeutic outcomes when delivered through nanoparticles.

Current research Obstacles and future perspectives

• Challenges include the quick removal of nanoparticles from joint spaces and difficulties in scaling up for clinical application.

• Future studies should focus on developing biocompatible coatings, enhancing retention mechanisms, and creating personalized formulations for patients.

• Gene therapies and biologically functionalized nanoparticles show potential for treating complex arthritis cases.

Conclusion

• Polymeric nanoparticles offer a revolutionary method for treating arthritis, providing targeted, sustained drug delivery while minimizing side effects.

• Progress in nanotechnology and biomaterials is essential for advancing these systems into clinical use and enhancing patient outcomes.

1. Introduction

Arthritis is a group of conditions involving inflammation and joint pain [1,2]. The cases of arthritis vary widely; however, the most common forms of arthritis include osteoarthritis, rheumatoid arthritis, and gout [3,4]. Arthritis can affect people of all ages, including youngsters, but the odds are greater in adults who are aging. Osteoarthritis is the most frequent type of arthritis, and it occurs when the cartilage and bone deteriorate because of the daily use of the joints. Rheumatoid arthritis contrasts with an autoimmune condition in which the immune system erroneously attacks joints, which is different from the case of osteoarthritis [5]. Gout is marked by the development of sudden and acute episodes with signs of joint pain, swelling, and redness, which are frequently caused by uric acid crystal deposition [6].

Center for Disease Control and Prevention, for instance, asserts that more than 54 million adults in the USA have arthritis or rheumatic conditions (www.cdc.gov). Arthritis affects many people around the world, about 350 million now (Global RA Network). Knee osteoarthritis alone affected an estimated 654.1 million individuals aged 40 and older globally in 2020 [7]. Additionally, the prevalence of arthritis is projected to increase significantly. For example, in the United States, more than 23% of adults are affected by arthritis, and it is expected that by 2040, approximately 78.4 million adults (or 25.9% of the adult population) will have received a medical diagnosis of arthritis [8]. Further, the prevalence of arthritis among Indians aged 45 and above was found to be 9.36%, with higher rates in females (11.03%) compared to males (7.49%) [9]. The burden of osteoarthritis in India has increased substantially, with the number of affected individuals rising from 23.46 million in 1990 to 62.35 million in 2019 [10].

With the increasing burden, current arthritis therapies are still inadequate due to systemic side effects, poor compliance, and poor targeting of inflamed joints. Recent advances in polymeric nanoparticles have demonstrated the potential to overcome these challenges; however, comprehensive reviews focusing on their application specifically for arthritis management are limited.

This review provides an in-depth analysis of modern advances in drug delivery systems using polymeric nanoparticles for the treatment of arthritis. It highlights the unique benefits of these systems against current therapeutic challenges, including design, functionality, and practice implications. Moreover, this review integrates recent findings, identifies key issues, and potential future research directions to advance the development of novel, safe, and effective therapeutic strategies for treating arthritis.

1.1. The pathophysiology of arthritis

There is a disparity between various types of arthritis due to their etiology. However, some of the fundamental mechanisms are implicated in all forms of arthritis. In osteoarthritis, structural alterations of the cartilage such as deterioration and degradation [11]. This may be the result of the buildup of mechanical stress, aging factors, inherited predisposition, and the imbalance of metabolism. Cartilage loss occurs because the joint gets worn out by reduced cushion and increased friction by the bone. Although inflammation is not as profound in osteoarthritis as in other kinds of arthritis, synovium cells may be in a low-grade inflammatory state due to the synovium membrane lining the joint [12]. Some of the prominent inflammatory mediators, like cytokines and enzymes, lead not only to the damage of the cartilage but also to joint inflammation [13].

In rheumatoid arthritis, the immune system wrongly enters the joint into the battle with the synovial membrane, which lines the joints. Autoantibodies, like rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, are the antigenic compounds synthesized [14]. In other words, these antibodies can activate the immune system cells, which then trigger the inflammatory process. Inflammatory cells of different kinds are trapped inside the synovium, which leads to synovitis of the joint. This subsequently triggers the release of proinflammatory cytokines, which include Tumor Necrosis Factor-alpha (TNF-α), IL-1, and IL-6 [15]. They are thus thought to be involved in the initiation of a chronic inflammatory state and contribute to the destruction of the joints by the inflammatory cells. In RA, the chronic inflammatory condition leads to the formation of a pannus tissue that is structurally abnormal. The pannus has an extremely vascular and transgressive nature with the capability of eroding the cartilage, bone, and other structures of the joints. Incrementally, this results in deformities of joints, bone loss, and finally, a functional disability of the joint.

Deposition of monosodium (MSU) urate crystals in the joints is a characteristic of gout and is associated with inflammation [16]. Hyperuricemia will create MSU crystals. MSU crystals can be facilitated at certain temperatures and pH. On activating macrophages and neutrophils, MSU crystals activate the NLRP3 inflammasome that leads to the release of pro-inflammatory cytokines, most importantly IL-1β [17]. Moreover, chronic gout is characterized by tophus formation, contributing to structural joint damage. In such respects, understanding the mechanisms gives way to the potential development of targeted therapies in the management of both acute and chronic gout.

2. Current approaches for the treatment of arthritis

Arthritis treatment recognizes a plethora of techniques that help in relieving the symptoms, winding down inflammation, managing pain, enhancing joint function, and retarding the disease.

2.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed pain and inflammatory-suppressing drugs [18]. Examples include ibuprofen, naproxen, and celecoxib. In acute gout, some evidence exists that NSAIDs could yield results as effective as systemic glucocorticoids both in relieving pain and enhancing function [19]. For osteoarthritis, first-line therapy is also established, with choices determined by the underlying factors in the patient plus the drug’s benefit-risk profile [20]. According to Vasilyuk et al. [21], the parenteral NSAID is the phenylbutazone in AMBENIUM^®; it acts both effectively and safely in the treatment of gouty attacks, holding a favorable risk-benefit ratio in comparison to other NSAIDs. However, the use of NSAIDs must always be determined by careful patient evaluation and by periodic reassessment of treatment.

2.2. Disease-modifying antirheumatic drugs (DMARDs)

Used primarily for rheumatoid arthritis, DMARDs, such as methotrexate, sulfasalazine, and hydroxychloroquine, slow disease progression by targeting the underlying inflammatory processes [22]. The main conventional DMARDs include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine [23]. These drugs improve RA symptoms, reduce joint tenderness and swelling, and slow joint damage progression. Methotrexate has been the first-line DMARD due to its high efficacy not only as monotherapy but also in combination with other agents [24]. Although conventional DMARDs are still considered the mainstay of RA therapy, biologic DMARDs, such as infliximab and rituximab, have better efficacy with fewer side effects [25]. Dentists must be aware of possible interactions between DMARDs and common dental drugs used to avoid adverse reactions.

2.3. Corticosteroids

Corticosteroids are typically used for acute inflammation in both rheumatoid arthritis and gout flare-ups. They can be given either orally or via the administration of injections, either intra-articular or intramuscular. Some of the common ones are Prednisone and methylprednisolone [26]. Corticosteroids are useful in acute gout and rheumatoid arthritis as they are pain relievers similar to NSAIDs but with fewer side effects [27,28]. There is no meaningful difference in efficacy between corticosteroids and NSAIDs when it comes to acute gout. However, safety profiling will be more favorable with corticosteroids because they carry less chance of issues such as indigestion, nausea, and vomiting. Oral prednisolone 30 mg per day for 4–5 days is the most common dosing in acute gout. However, traditional pharmacological therapy may be inadequate in those with co-morbid conditions, including chronic renal failure or diabetes mellitus; thereby, there is a need for developing new therapeutic agents and treatments [29]. New delivery sites are being investigated, including liposomes, polymeric nanoparticles, and inorganic nanoparticles, to improve corticosteroids’ pharmacotherapy, thereby decreasing the side effects.

2.4. Urate-lowering drugs for gout

Specific to gout, medications like allopurinol, febuxostat, and probenecid lower uric acid levels, reducing the frequency of gout attacks and preventing tophi formation [30]. Urate-lowering therapy (ULT) is crucial for managing gout, with several drugs available. Allopurinol, a well-studied xanthine oxidase inhibitor, is effective but can cause adverse reactions like skin rash [31]. Febuxostat is a second-line ULT drug that is generally well tolerated and effective in achieving the goals of urate-lowering, even in patients who cannot tolerate allopurinol [32]. It has improved quality-of-life markers as well as kidney function in patients with gout. Other options for using ULTs include probenecid, lesinurad, and pegloticase, each with individual considerations for their use [33].

In addition to this, physical therapy is also given to enhance joint function, strengthen muscles, and improve flexibility with exercise, heat/cold therapy, and other modalities [34]. Assistive devices, such as braces or orthotic inserts, provide support and pain relief [35], while lifestyle modifications, such as exercise, weight management, and dietary changes, also facilitate improved outcomes. Joint replacement surgical options may be an option for more severe osteoarthritis or when other medical interventions are not feasible [36]. Many antirheumatic drugs are administered orally as tablets, capsules, or liquid preparations. They are ingested and then absorbed into the bloodstream through the gastrointestinal tract. In some cases, topical agents can be applied directly to the skin over the involved joints. Formulations include creams, gels, ointments, or patches. Local drug applications, like topical NSAID gels and capsaicin creams, can be relied upon to produce localized effects by reducing pain and inflammation [37]. Table 1 summarizes common treatments and medications for different arthritis types and their administration routes to provide a comprehensive overview of therapeutic approaches for osteoarthritis, rheumatoid arthritis, and gout.

Table 1.

Common treatments, medications, and administration routes for arthritis types.

Arthritis type	Treatment category	Medications/examples	Administration route
Osteoarthritis	NSAIDs	Ibuprofen, Naproxen, Celecoxib	Oral, Topical
	Intra-articular Injections	Hyaluronic acid	Intra-articular
	Corticosteroids	Prednisone, Methylprednisolone	Oral, Intra-articular, Intramuscular
	Lifestyle Modifications	Weight management, physical therapy	–
	Topical NSAIDs	NSAID gels, Capsaicin creams	Topical
Rheumatoid Arthritis	DMARDs	Methotrexate, Sulfasalazine, Hydroxychloroquine, Leflunomide	Oral, Intramuscular
	Biologics	Adalimumab, Tocilizumab, Etanercept, Sarilumab	Intravenous, Subcutaneous
	Biologic DMARDs	Infliximab, Rituximab	Intravenous
	Corticosteroids	Prednisone, Methylprednisolone	Oral, Intra-articular, Intramuscular
Gout	NSAIDs	Indomethacin, Naproxen, Phenylbutazone	Oral, Topical, Parenteral
	Urate-lowering drugs	Allopurinol, Febuxostat, Probenecid, Lesinurad, Pegloticase	Oral
	Corticosteroids	Prednisone, Colchicine	Oral, Intra-articular, Intramuscular

2.5. Limitations of current treatment methods

Though the distinct modes of drugs for arthritis may be effective, there are still certain clauses to them. Oral medications can cause an unspecific effect on the whole body and induce side effects such as gastrointestinal problems, e.g., abdominal pain, gastritis, abdominal ulcers, kidney problems, or cardiovascular risks. Hepatic first-pass metabolism significantly influences the bioavailability of oral medications, and their absorption can vary from one individual to another, with food intake or drug interactions impacting their efficiency [38]. The common GI side effects include ulcers and bleeding. Diclofenac causes duodenal ulcers or erosive gastritis in 2.05% of cases [39]. Cardiovascular risks are also an issue due to NSAIDs; for example, rofecoxib led to acute myocardial infarction among 2.12% of users. Renal complications are also significant, particularly acute kidney injury [40]. The mechanisms behind NSAID-induced GI damage include reduced blood flow, increased gastric motility, and decreased mucus secretion.

Topical medicaments may not be able to penetrate deep enough into the target joint tissues, and this may become a problem, especially in cases of deep joint inflammation or widespread arthritis. These acupuncture methods usually require joint surfaces and are applied to local pain; they are not practical methods to apply to multiple joints in depth [41]. While injections may be useful for extremely fast and designated relief, they may only be for a short time duration. For instance, the joint injections of corticosteroids may work for just a few weeks to months and subsequently demand another injection [42]. Intravenous infusions are the most usual type, which requires the patient to report to a medical facility—e.g., infusion center or hospital—often for an entire day, which may not be doable for people who have employment or with limited mobility resources. Subcutaneous injections at home are more convenient but require adequate training, and this type of injection may not be suitable for people who have difficulty tolerating discomfort.

Similarly, Allopurinol, the first-line urate-lowering therapy for gout management, poses a risk of adverse reactions, particularly in patients with renal impairment [43]. Mild adverse effects are skin rashes, diarrhea, and nausea, whereas more severe but less common adverse reactions include Stevens-Johnson syndrome [44]. The main causes of major adverse effects are ethnicity, the presence of HLA-B*5801 genotype, kidney dysfunction, initiation dose, and diuretic use.

3. Targeted drug delivery for arthritis treatment

Recent advancements in targeted drug delivery systems have been shown to overcome the obstacles above and improve treatment efficiency. As an example, local drug delivery systems, such as intra-articular injections or implants, can be injected into the affected joints or implanted for the delivery of medications. Targeted drug delivery is of great benefit because the medicine only works on the inflamed area, and at the same time, it reduces the side effects on the whole body. Furthermore, the nanoparticles can be designed in a way that they stick to the inflamed joints only and transport the drugs [45]. They can retain drugs in joints, enhance drug absorption through joint tissues, and highly boost the therapeutic effects. Biotechnology has become a part of the arsenal of scientists who are trying to reveal new biological remedies and gene therapies to cure arthritis. These treatments are designed so that the immune response is changed or, at molecular levels, the damaged joint tissues are repaired so that new treatment approaches are more exact and specific. New research can address the issues of arthritis, which were not possible in the past. Chondrogenesis is the process when cells turn into cartilage, and substances that support this process are called chondrogens. They are produced by the cells in the body; therefore, they affect the inflammatory process. They are the mediators of anti-inflammatory cytokines, and they are called cytokines. g. BMP-7 and FGF-18 are some of the proteins that were detected in the bone matrix. Also, the identified essential parts of the immune response, such as the pro-inflammatory cytokines from the IL-1 family (IL-1 receptor antagonist and IL-1 receptor antibody) and the modulators of the Wnt pathway, which is involved in cellular proliferation and tissue regeneration. For example, it has also been demonstrated that this affects the lives of the local communities [46]. Besides, the gene therapy techniques that are nucleic acid-based, such as pDNA, mRNA, siRNA, aptamers, and antisense oligonucleotides, are also demonstrating considerable progress in the way of targeting the pathways of joint tissue damage.

3.1. Bioactive compounds in arthritis treatment

Bioactive compounds are derived from natural sources, with recognized benefits including anti-inflammatory, antioxidant, and immunomodulatory properties [47]. These molecules proved to be vital in the regulation of inflammatory diseases, most importantly, arthritis, hence facilitating the inflammation-reduction process that slows the disease progression process [48]. Marine-derived bioactive compounds have been promising in the treatment of rheumatoid arthritis and, therefore, can be considered potential alternatives to synthetic drugs due to fewer side effects [49]. Black cumin, or Nigella sativa, contains bioactive ingredients that have shown therapeutic effects in rheumatoid arthritis, with anti-inflammatory and immunomodulating properties [48]. Quercetin is known as a flavonoid dietary that has immense joint-protective effects in preclinical models of rheumatoid, gouty, and osteoarthritis [50]. Seven bioactive constituents isolated from the leaves of Bougainvillea spectabilis—include secologanin dimethyl acetal, α and β-amyrin, α and β-amyrin acetate, kaempferol, and kaempferol-3-O-rhamnoside)—showed very potent anti-rheumatoid arthritis activity [51]. Besides, these studies further show that natural bioactive compounds have a potential future in the development of novel drugs that are safer against this disease.

3.2. Nanoparticles for targeted treatment of arthritis

Nanocarriers and polymeric nanoparticles have eased the treatment of arthritis with great results [52]. Nanoparticles can be modified to target affected joints in arthritis patients in an arm-to-arm manner. This is realized by the way the surface of nanoparticles is being modified with ligands or antibodies that have specificity toward the sites of inflammation. Through the delivery of drugs to the affected area, nanoparticles can be considered as a method that reduces the overall exposure to the system and amplifies the accumulation of drugs at the site of action. Along with minimizing the side effects of conventional arthritis treatments, nanoparticles can also be used [53]. Through drug delivery to the inflamed joint, nanoparticles prevent systemic exposure to the drug; thus, systemic adverse effects are reduced (Figure 1). Besides the matter, targeted delivery makes it possible to use lower drug doses and minimize the toxicity caused by drugs. By using the polymeric nanoparticles, one can encapsulate the drugs used for arthritis treatment [54]. Encapsulation protects the drug from degradation, increases its stability, and boosts solubility. This mechanism increases the drug concentration at the target site, thus improving the quality of therapy. Moreover, nanoparticles of polymer can be constructed to deliver the trapped drugs over a certain period. The nanoparticle composition and size can be tuned to amend the drug release rate. This continuous drug release pattern enables the use of therapeutic drug levels over an extended period, which, in turn, reduces the frequency of drug administration and thereby improves medication adherence. Polymeric nanoparticles may be designed to deliver multiple drugs at once by which poly-therapies are possible to cure arthritis [55]. This strategy would bring about the synergic effect and the improved response of the therapy by applying drugs that have various mechanisms of action.

Figure 1.

Targeted drug delivery using polymeric nanoparticles in arthritis treatment: the inner circle illustrates the components of the delivery system, i.e., drug loaded in polymeric nanoparticles. This loading helps in systemic and targeted delivery of drug to arthritic joints. The outer circle represents the important protective role of polymer matrix of protecting drug from the local environment, protecting its stability, and ensuring targeted delivery, hence increasing efficacy in treatment.

Chitosan-based nanocarriers modified with hydrophobic amino acids hold promise for better encapsulation and controlled release of hydrophobic pharmaceuticals, thereby ensuring better bioavailability [56]. Still, these carriers are likely to face issues related to bioavailability in more interior tissues, and in vivo efficacy data regarding arthritis are very limited. Future studies may focus on the functionalization of the nano-carrier to enhance more penetration into joint tissues, followed by in vivo efficacy studies for validation in arthritis models. Further, HA-functionalized nanoparticles have demonstrated improved targeting to inflamed tissues by binding to CD44 receptors, showing potential for enhanced retention and controlled release in arthritis treatment [57]. While these nanoparticles improve targeting, limitations include challenges with scalability and potential immunogenic responses. Exploring alternative biocompatible coatings that mimic HA’s targeting capabilities could mitigate these limitations, facilitating large-scale production. Nanoparticles have shown significant promise in arthritis treatment by enhancing drug delivery to inflamed joints while reducing systemic toxicity and improving bioavailability [58]. However, challenges such as rapid clearance from the joint space and limited deep tissue penetration persist, limiting sustained drug efficacy. Future research should focus on developing nanoparticles with improved retention in the synovial cavity and enhanced penetration capabilities for increased therapeutic effects.

4. Literature search and selection of articles

We performed a comprehensive literature review to identify relevant studies on polymeric nanoparticles in the treatment of arthritis. Major databases, namely PubMed, Scopus, and Web of Science, were systematically searched utilizing keywords including “polymeric nanoparticles,” “arthritis treatment,” “bioactive compounds,” and “targeted drug delivery.” The results were further refined through the use of Boolean operators. Studies were selected based on their focus on recent advancements in nanoparticle-based therapies, delivery mechanisms, and potential applications in arthritis. Articles were further screened for relevance, prioritizing studies published within the last decade to ensure an up-to-date synthesis of current research.

5. Polymeric nanoparticles as nanoscale carriers: synthesis and structure

Polymeric nanoparticles are very small particles of size in the nanometer range and are made from biocompatible or biodegradable polymers like poly (lactic-co-glycolic acid) (PLGA) [59]. Such nanoparticles are currently studied intensively in scientific research and industrial applications because of their unique properties and the possibility of their use in different fields, including medicine, electronics, and environmental science.

5.1. Synthesis methods

The synthesizing method of polymeric nanoparticles will involve the creation of polymer chains and the subsequent nanoparticle formation using different techniques (Figure 2). Such methods are emulsion polymerization, nanoprecipitation, solvent evaporation, and template synthesis [60]. The choice of the synthesis technique is related to the size, shape, and properties of the nanoparticles, which are highly essential.

Figure 2.

Schematic representation of the synthesis of loaded polymeric nanoparticles: the protocol begins with selection of appropriate polymers and drug candidates. To create an organic phase, the medication and polymer are first dissolved in an organic solvent. An oil-in-water emulsion is then formed by emulsifying this phase under stirring or sonication into an aqueous phase that have a stabilizer. After that, the organic solvent is carefully evaporated, forming solid polymeric nanoparticles that encapsulate the medication. After that, the nanoparticles are collected, washed, and evaluated for stability, encapsulation efficiency, and size in relation to drug delivery applications.

In the emulsion polymerization approach, monomers are emulsified in a solvent, followed by the initiation of polymerization, leading to the formation of nanoparticles [61]. Parameters of reaction such as monomer concentration, initiator type, and stirring speed can be adjusted to bring the proper size and properties of nanoparticles.

Nanoprecipitation is also known as the solvent displacement technique, in which a water-miscible organic solvent is utilized to dissolve the polymer. This solution is then rapidly added to an aqueous solution that can be termed a non-solvent to cause immediate precipitation of the polymer and the formation of nanoparticles. In contrast to the evaporation of the solvent, the organic solvent dilutes in this process after diffusing into the aqueous solution [62].

The solvent evaporation technique, alternatively, entails the dissolution of the polymer in a volatile organic solvent that is immiscible with water, followed by the emulsification of this solution into an aqueous phase [63]. To preserve the emulsion, stabilizing agents are incorporated, after which the organic solvent is eliminated via evaporation, yielding solidified nanoparticles. This methodology is extensively employed for the encapsulation of hydrophobic pharmaceuticals and facilitates meticulous regulation of particle dimensions and drug loading efficacy. The properties of the nanoparticles vary with the evaporation rate, polymer concentration, and solvent type.

In a template-assisted method, templates, for example, emulsion droplets and solid particles, could guide the formation of nanoparticles [64]. Template-assisted synthesis uses hard or soft templates with precise control over nanoparticle formation. Soft templates, such as emulsion droplets, can confine the synthesis process to allow for size-controllable production of nanoparticles without a separate template [65]. Template synthesis has advantages over other methods with precise control of nanoparticle size, shape, and structure, based on which this method is immensely used for the production of nanomaterials. Table 2 summarizes various polymeric nanoparticles used for arthritis treatment, including synthesis methods and key findings for each type.

Table 2.

Polymeric nanoparticles for arthritis treatment.

Nanoparticle type/composition	Target drug/bioactive compound	Synthesis method	Key findings/benefits
Chitosan-based nanoparticles	Methotrexate	Self-assembly	Improved stability, targeted delivery to inflamed joints
PLGA nanoparticles	Betamethasone	Nanoprecipitation	Sustained release, reduction in inflammation in RA models
PEG-coated PLA nanoparticles	Tocilizumab	Emulsion polymerization	Enhanced circulation time, localized delivery to inflamed synovium
Hyaluronic acid-modified nanoparticles	Interleukin-6	Solvent evaporation	Prolonged drug action, specific targeting of inflamed joint tissues
Dextran sulfate nanoparticles	Dexamethasone	Template-assisted synthesis	Reduced systemic side effects, controlled release, effective for RA

Concerning the development of polymeric nanoparticles, the most common natural polymers used are chitosan, hyaluronic acid, gelatin, albumin, and dextran. Chitosan is the byproduct of chitin, a material from crustaceans’ exoskeletons. Chitosan nanoparticles are known these days for good biocompatibility and biodegradability [66]. They can be encapsulated with anti-inflammatory drugs and growth factors very effectively and, hence, become an option with great promise in arthritis treatment. Also, hyaluronic acid is a main component of synovial fluid that provides the joint with smooth motion and shock absorption [67]. It is employed as a stabilizer and a targeting ligand of the polymeric nanoparticles. Gelatin is extracted from collagen, which is the major protein present in the connective tissues. It can make nanoparticles using different techniques, including emulsification or coacervation [68]. Nanoparticles based on gelatin provide good biocompatibility, and this feature can be modulated according to the requirements for controlled drug release. Human serum albumin is a biocompatible and biodegradable protein that is the basis of the nanoparticle-based drug delivery system. It enables the incorporation of functional groups, which makes it better to load drugs that target arthritis treatment. Dextran is a polysaccharide obtained from sucrose. Dextran-based nanoparticles have proved themselves capable of encapsulating anti-inflammatory drugs, and they have shown immense efficacy in the treatment of arthritis [69]. These natural polymers are of great advantage because they are biocompatible, biodegradable, low toxic, and easy to be functionalized for specific drug delivery.

Similar examples are polymers such as PLGA (poly (lactic-co-glycolic acid)), PEG (polyethylene glycol), PVP (polyvinylpyrrolidone), PCL (polycaprolactone), and many others. PLGA is an FDA-approved biodegradable, biocompatible polymer derived from lactic acid and glycolic acid [70]. PEG is a hydrophilic monomer that is generally used to increase the stability and improve the biocompatibility of polymeric nanoparticles. Likewise, it lowers the extent of nonspecific interactions with the biological molecules. PCL belongs to a group of water-repellent, biodegradable polyesters.

5.2. Structure of polymeric nanoparticles

The structure of polymeric nanoparticles will change depending on the synthesis method and the polymer selection. Nevertheless, they usually comprise some basic points as specified in the subsequent paragraphs. The core is the central area of the nanoparticle, which may be made of the polymer, the cargo itself, or the encapsulated agents like drugs, imaging substances, or other healing molecules. The main material and its properties exert an impact on the stability and release devotion of the nanoparticles. The nanoparticle in the center is frequently covered with a layer of polymer or surfactant. The coating here occurs by preventing the aggregation of nanoparticles and providing stability in different environments. In addition to that, the polymer nanoparticles are functionalized with ligands or targeting molecules on their surface. Due to the presence of these functional groups, specific interactions with target cells or tissues can be promoted, which eventually aims to achieve targeted drug delivery and improved therapeutic efficiency. The size and shape of those nanoparticles made from polymers can be changed during synthesis, and they will influence the interaction with the biological system, biodistribution, and cellular uptake in a significant way. For the delivery of drugs, the most important is the effectiveness of encapsulating the cargo (e. g., encapsulation of drugs (medicines) is crucial for delivering the effects of therapy (Figure 3).

Figure 3.

Comparison of drug embedded versus drug encapsulated in polymeric nanoparticles: the medicine is evenly dispersed throughout the polymer matrix in the embedded type, creating a homogenous core. This configuration permits regulated release and improves medication stability. The drug is adsorbed onto the polymer matrix’s surface in the loaded state, which speeds up release but may also expose the drug to environmental influences.

Moreover, the polymeric nanoparticles can be devised to have stimuli-responsive, such as pH-responsive, temperature-responsive, or enzyme-responsive properties. This gives the drugs the opportunity of controlled release in response to physiological or environmental causes, thus making them more penetrating the medical area. There was one study where polymeric nanoparticles were designed to deliver siRNA to inflamed tissues; this was done in rheumatoid arthritis [71]. The nanoparticles were composed of pH-sensitive polymer PK3, PEG-lipid poly(lactide-co-glycolide). In its core was DOTAP/siRNA. In laboratory tests, the rate of released siRNA from nanoparticles changed at pH levels, and most of it was released at pH 5.

6. Polymeric nanoparticles in drug delivery for arthritis treatment

Nanomedicine delivery systems have turned into state-of-the-art instruments in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA). These systems can focus on pathological features in RA joints, such as increased vascular permeability and macrophage infiltration. One of the important mechanisms that helps this targeting is the ELVIS effect, which ultimately makes the nanocarriers concentrate and release the medications in inflamed synovial tissues [72]. Nanoparticles that carry drugs get filtered out by the spleen and the liver; this helps to lower their circulation times in RA patients. Concerning the drug delivery process, several other modifications have been created to improve the process and reduce the off-target effects by using a material such as surface coating with PEG and chitosan and biomimetic nanocarriers. Identification of nanocarriers loaded with drugs such as celastrol, benzoyl aconitine, methotrexate, and Notch1 siRNA for the in vitro and in vivo studies resulted in the successful targeting and suppression of inflammatory cytokines in the RA joints. In the same manner, polymeric nanoparticles, such as chitosan and PLGA processes, are expected to play an important role in the treatment of OA [73]. These nanoparticles can regenerate tissues with low toxicity in OA preclinical models, modifying the inflammation process through mediators such as proteolytic enzymes, proinflammatory cytokines, and reactive oxygen species (ROX). Enhancing drug delivery efficacy by applying PEG, chitosan, and stimuli-responsive nanomedicines, followed by the minimization of the off-target effects, is being investigated [74].

Research corroborates the investigation of specific nanocarriers, which has disclosed the efficacy of nanocarriers in arthritis therapy. For example, the stealth nano steroids loaded with betamethasone using PLA/PEG-PLA polymers are very effective in experiments on arthritis, where their prolonged release at the inflamed joint seems to be the reason for their success [75]. The nanoparticles of mefenamic acid, which are fabricated by applying the technique of solvent evaporation, have been shown to produce better therapeutic results in RA since they are nano-sized, stable for a long and release the drug in a controlled manner. Further, Ethyl cellulose and Eudragit were found to provide sustained release profiles, with ethyl cellulose showing more rate-retarding properties than Eudragit L100 [76].

For diagnosis and treatment, a new nano platform of TCZ-PNPs, which combines tocilizumab (TCZ) and PNPs for NIR-II photoacoustic molecular imaging, provides a very effective strategy for RA theranostics and therapeutic monitoring [77]. Concerning this, the methotrexate (MTX) oral bioavailability was improved by utilizing the core-shell polymeric nanoparticles via self-micellization and ionotropic gelation technique, resulting in improved pharmacokinetic profiles and therapeutic efficacy in the arthritis treatment. Coated nanoparticles made of Chitosan-Hyaluronic Acid-Biodegradable polymeric agents as well have also been established to be very effective in fixing and capturing interleukin-6 (IL-6) in arthritic disease treatment.

The encapsulation of MTX and HA in the polymeric nanoparticles has significant efficacy in targeted therapy for rheumatism. The system was made up of nanoparticles of a polymer called PLGA, which were filled with MTX and HA; these nanoparticles target inflamed synovial tissue cells (Figure 4). ¹⁷⁷Lu isotope was employed for radiotherapy, being bound to DOTA. The nanoparticle system was able to maintain encapsulation of MTX and to do the efficient ¹⁷⁷Lu radiolabeling, as well as polymeric nanoparticles loaded with alpha keto-glutarate (aKG) in their polymer backbone could effectively regulate T-cell responses in RA providing one more treatment option besides. In murine CIA, three low doses of MTX and two doses of the encapsulated peptide paKG significantly diminished the symptoms of arthritis. The therapy decreased the proinflammatory antigen-specific T helper type 17 (TH17) response and elevated the anti-inflammatory Treg response when splenic cells from treated CIA mice were challenged with the CIA self-antigen. Additionally, nanocrystalline biopolymeric nanoparticles encapsulating MTX and dexamethasone have shown better efficacy with fewer side effects, and thus, they are the most appropriate treatment for arthritis.

Figure 4.

Schematic representation of the mechanism of drug delivery in the treatment of arthritis using polymeric nanoparticles. Uptake of drug loaded polymeric nanoparticles can occur in two ways: Receptor-ligand interactions mediate active uptake or increased permeability and retention (EPR) facilitates passive uptake. After internalization, the drug is released by the nanoparticles in response to pH-sensitive triggers, redox conditions, or reactive oxygen species (ROS) in the macrophage microenvironment. The medication that is released suppresses NOTCH and BTK signaling pathways and downregulates pro-inflammatory cytokines like TNF-α, IL-1, and IL-6. This combination action demonstrates a focused treatment approach by effectively reducing inflammation and modulating immunological responses.

The polymeric nanoparticle delivery systems provide various potential solutions for the arthritis treatment which focuses on the specific pathologic features and delivers drugs with improved efficacy that avoid the side effects. Studies discussed in this chapter also showcased the wide variety of nanocarriers and modifications tested. This way, we are not too far from better treatment options that would be more targeted for arthritis.

6.1. Polymeric nanoparticles in delivery of bioactive compounds for arthritis treatment

The oral form of bioactive natural substances frequently suffers from several challenges including the following: limited water solubility, instability in the stomach, extensive metabolism, short action duration, and poor bioavailability [70]. To overcome these challenges, scientists have chosen nanocarriers, especially polymeric nanoparticles, as the widely employed devices for the delivery of bioactive compounds. These nanoparticles protect bioactive substances from entering the organism through the mouth and improve their interaction with the stomach epithelium. Due to the larger effective surface area, the dissolution rate and interaction with tissues are significantly improved. As mentioned earlier, surface modifications of polymeric nanoparticles have been adequately and efficiently carried out in the case of parenteral administration. Using targeting molecules and PEGylation, such nanoparticles can directly target certain tissues, stay longer in the circulatory system, and even pass through the blood-brain barrier. Therefore, drug delivery to the brain can be executed through multiple means, including the penetration of the blood-brain barrier.

This section dwells on the employment of polymeric nanoparticles in drug delivery for arthritis therapy, which has special attention to some commonly used bioactive compounds and their conjugated polymeric nanoparticles. TwHF (Triptergyium wilfordi Hook F), a natural product well studied, is one of the plant extracts that are preferred for the treatment of arthritis [78]. TwHF can inhibit a wide range of proinflammatory mediators, and it has already been tested in clinical practice either alone or in combination with the conventional therapy MTX. Along with their two triptolide and celastrol bioactive components, they can prevent inflammation and bone loss. The in vivo performance of TwHF-loaded SLN has been investigated in rats with arthritis. Comparatively, it has been found that they significantly reduced inflammation and showed less hepatotoxicity than free TwHF, indicating their better safety profile and, hence, their potential for clinical use.

Also, curcumin, a natural compound with antioxidant and anti-inflammatory characteristics, has tremendous potential to treat arthritis [79]. Nonetheless, its hydrophobic nature limits its solubility and circulation time and results in cytotoxicity when it is used in its free form, which is why its use in higher concentrations is restricted. The researchers had to tackle these challenges by inventing curcumin-loaded polymeric nanoparticles using a bioactive terpolymer. Such nanoparticles supplied gradual drug release and exhibited antioxidant and anti-inflammatory activities on human articular chondrocytes and RAW264. The study also confirmed immunogenicity and biocompatibility of the seven cultures in vitro. Biocompatibility was also given in a rat model upon subcutaneous injection. It also demonstrated the use of curcumin-loaded nanoparticles together with the polymeric material CMCAB (carboxymethyl cellulose acetate butyrate) through a process called flash nanoprecipitation.

Resveratrol, a polyphenol isolated from red grapes, is another possible arthritis treatment because of its anti-inflammatory and bone-protecting effects [80]. It has shown its capability to inhibit arthritis in animal models, and it has been studied for options to eliminate synovial inflammation and bone restructuring. Researchers have looked at the in vitro impact of the co-encapsulated resveratrol and curcumin in the lipid-core nanocapsules with the help of a CFA-induced arthritic rat model. The triple encapsulation of the polyphenols was the most effective, with a 37-55% reduction of edema over the period from day 16 to day 22 after the induction of arthritis. Moreover, this therapy suppressed the histological changes that normally occur in the synovial fluid, cartilage, and bone structure that are characteristic of arthritis. Also, hepatotoxicity of polyphenols did not appear since there was no change in important hepatic biochemical markers. Table 3 provides an overview of bioactive compounds delivered via nanoparticle formulations for enhanced therapeutic effects in arthritis.

Table 3.

Nanoparticle-based bioactive compound delivery for arthritis.

Bioactive compound	Nanoparticle type	Target mechanism	Study results
Triptolide (from Tripterygium wilfordii)	Solid Lipid Nanoparticles (SLN)	Anti-inflammatory, bone protection	Reduced inflammation, lower hepatotoxicity compared to free Triptolide
Curcumin	Polymeric Terpolymer Nanoparticles	Antioxidant, anti-inflammatory	Controlled release, effective in human chondrocyte models
Resveratrol	Lipid-Core Nanocapsules	Synovial inflammation, osteoprotection	Reduced edema, no liver toxicity observed in rat arthritis model
Alpha-Ketoglutarate	PLGA Nanoparticles	Modulation of T-cell responses	Improved immune response, reversal of arthritis symptoms in mice
Methotrexate + Hyaluronic Acid	PLGA Core-Shell Nanoparticles	Antirheumatic, targeting inflamed synovium	Enhanced bioavailability, prolonged drug action in animal arthritis models

7. Current research obstacles and future perspective

Although promising, the applications of polymeric nanoparticles for arthritis treatment are currently limited by several practical challenges. Rapid clearance from the synovial cavity limits the time course of the therapeutic effects, therefore requiring higher dosing frequency. An important goal is to prolong retention of the nanoparticles within joint tissues to improve the prospects for patients. Besides, hydrophobic drugs also pose formulation challenges due to their low solubility in aqueous conditions. Amphiphilic polymers or hydrophobic surface modifications might enhance the encapsulation and controlled release of these drugs.

A major issue is the scale-up of the manufacturing process since the size and functional consistency over large batches of production must translate to the clinic. With such, functionalized nanoparticles bearing HA or targeting ligands can provide better targeting capabilities. However, they often suffer from issues with immunogenicity and manufacturing difficulty. To overcome these, future research may focus on biocompatible, scalable coatings and reproducible manufacturing protocols.

In the future, the targeting of polymeric nanoparticles with biological agents or gene therapies may be the best approach to the more complex cases of arthritis, and tailored formulations prepared according to the specific individual patient conditions will significantly improve the therapeutic outcome. Advances in biomaterials, such as biocompatible and biodegradable polymers, are expected to improve nanoparticle stability, safety, and efficacy, paving the way for more effective arthritis treatments.

8. Conclusion

Polymeric nanoparticles present considerable potential as sophisticated drug delivery mechanisms for arthritis, which profoundly impacts individuals’ quality of life. These nanoparticles facilitate targeted, prolonged, and customized treatment strategies that mitigate systemic adverse effects while enhancing therapeutic effectiveness. Their versatility permits the implementation of combination therapies, addressing the complex nature of arthritis and offering a route toward more holistic treatment approaches.

The translation of these nanocarrier technologies from preclinical research to clinical settings is necessary to establish their safety and therapeutic efficiency in human patients. Notably, advancement in the field of biomaterials science, individualized medicine, and effective strategical drug-combination methodologies utilizing polymeric nanoparticles may revolutionize the management of arthritis. Therefore, polymeric nanoparticles represent a significant step forward in arthritis treatment with huge potential to improve therapeutic outcomes and the quality of life of patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).