Role and uptake of metal-based nanoconstructs as targeted therapeutic carriers for rheumatoid arthritis

Abstract

Rheumatoid Arthritis (RA) is a chronic autoimmune systemic inflammatory disease that affects the joints and other vital organs and diminishes the quality of life. The current developments and innovative treatment options have significantly slowed disease progression and improved their quality of life. Medicaments can be delivered to the inflamed synovium via nanoparticle systems, minimizing systemic and undesirable side effects. Numerous nanoparticles such as polymeric, liposomal, and metallic nanoparticles reported are impending as a good carrier with therapeutic properties. Other issues to be considered along are nontoxicity, nanosize, charge, optical property, and ease of high surface functionalization that make them suitable carriers for drug delivery. Metallic nanoparticles (MNPs) (such as silver, gold, zinc, iron, titanium oxide, and selenium) not only act as good carrier with desired optical property, and high surface modification ability but also have their own therapeutical potential such as anti-oxidant, anti-inflammatory, and anti-arthritic properties, making them one of the most promising options for RA treatment. Regardless, cellular uptake of MNPs is one of the most significant criterions for targeting the medication. This paper discusses the numerous interactions of nanoparticles with cells, as well as cellular uptake of NPs. This review provides the mechanistic overview on MNPs involved in RA therapies and regulation anti-arthritis response such as ability to reduce oxidative stress, suppressing the release of proinflammatory cytokines and expression of LPS induced COX-2, and modulation of MAPK and PI3K pathways in Kuppfer cells and hepatic stellate cells. Despite of that MNPs have also ability to regulates enzymes like glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) and act as an anti-inflammatory agent.

Introduction

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disorder. It is characterized by the destruction of bone and cartilage inflammation at a synovial site, leading to enhanced mortality disability and reduced quality of life. (Song et al. 2021; Devi Dwivedi et al. 2023) Out of 100,000 of the total population, 40 persons are affected by RA, more significant than 0.5 to 1%. It commonly starts at the age of 40 to 60 years (Zheng et al. 2021). According to the Global Burden of Disease 2010, the prevalence of RA in women is almost three times greater than in males which is usually one female in 28 and one male in 59. RA can develop at any stage of life. Women between the ages of 30 and 60 are more likely than males to acquire RA (Brennan-Olsen et al. 2017). Advancement in RA therapy was associated with the joint damage, inhibition, control the progression of disease that required frequent and prolonged administration of drugs leading to systemic side effects and multi-organ dysfunction such as myocardial infarction, stroke, arteriosclerosis, and pulmonary fibrosis (Dolati et al. 2016). Besides these, it has also caused uveitis, sjogren syndrome, kidney and tissue damage, and constitutional syndrome, as well as peritonitis and tooth loss (Srivastava et al. 2017a). Current therapy of RA is oriented towards suppression of disease progression and joint inflammation. The major drawback of current treatment includes improper targeting, deposition at non targeted cell, relief for shorter duration only and adverse effects. Nanoparticles have been investigated as potential therapeutic agents to address the drawbacks of current treatments by facilitating the effective accumulation of the target medication and improving therapeutic success (Dwivedi et al. 2024). There are numerous nanoparticles available such as lipid, polymeric, metallic, and oxide metallic nanoparticles. However, lipid and polymeric nanoparticles lack long-term in vivo stability during systemic circulation and multifunctional applications. Metallic nanoparticles (MNPs), on the other hand, are sophisticated therapeutic materials with anti-arthritic characteristics, as well as enhanced in vivo stability when utilized therapeutically. This review focuses on the emerging therapeutic potential of metallic nanoparticles in RA treatment.

Rheumatoid arthritis

Pathogenesis

RA is a chronically systemic autoimmune disorder marked by an overabundance of inflammatory cells (B-lymphocytes, dendritic cells, macrophages, T-lymphocytes, and monocytes,) in the synovium, resulting in neovascularisation, synovial hyperplasia, and joint destruction and deformity, as well as cartilage and bone erosion. It usually affects minor joints of feet and hands but it can affect any joint and even other vital organs including the heart, lungs, skin and eyes. Severe joint pain, tenderness and stiffness of joints that worsen in the morning or after a period of inactivity, involvement of symmetrical joint, unsteady walking, and loss of mobility and function are all common signs and symptoms of RA. If remain untreated, RA can cause cartilage to deteriorate, shrinking joint gaps, and bone erosion, which can lead to additional rheumatic morbidities such osteoarthritis and osteoporosis. While the exact etiology of RA are still unknown. However, much scientific evidence proves that it is the combination of effects of genetic, immunological, environmental, and oxidative factors (Srivastava et al. 2017a) (Fig. 1). Inflammation at Synovial site is the most common symptom of RA, which is caused by a complicated interaction between the adaptive and humoral immune systems. The immune system of the body attacks joints, cartilage, and bones as the underlying mechanism. The expression of adhesion molecules (vascular cells adhesion molecule-1, VCAM-1, and v3 integrins, E-selectin) and the secretion of chemokines by activated endothelial cells of synovial micro-vessels attract inflammatory cells (macrophages, monocytes, lymphocytes, and dendritic cells) into the synovium. Excessive synovial cell proliferation (synovial hyperplasia) and increased synovial fluid volume apparently generate an internal hypoxic environment in the synovium, which stimulates angiogenesis in the synovium via activation of vascular endothelial growth factors (VEGFs). Blocking VEGF signalling is one of the most important molecular targets for RA therapy.

Fig. 1.

Causative factors of Rheumatoid Arthritis: Rheumatoid Arthritis are combination effects of four factors i.e. Immunological, Genetic, Environmental and Oxidative stress

Dendritic cells (DCs), which are recruited inflammatory cells in the synovium, play an important role in the induction and activation of T-lymphocytes by expressing numerous co-stimulatory molecules, chemokines, and cytokines. T-lymphocyte activation is dependent on two signals: the first is antigen presentation via DCs to T-lymphocytes in the synovium, and the second is the co-stimulatory interaction of DC cell surface proteins with CD28 proteins on T-lymphocytes. T-cell activation and downstream processes can be hampered by blocking co-stimulatory signalling by competitive suppression of CD80/86 (Roeleveld and Koenders 2015). Activated T-lymphocytes release variety of chemokines and cytokines, which stimulate macrophage-like synoviocytes and fibroblast-like synoviocytes (FLSs), leading to enhanced infiltration of monocytes and macrophages in the inflamed synovium to produce the most potent inflammatory cytokines like tumour necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. As a result of the positive feedback loop, these inflammatory cytokines activate T-lymphocytes, exacerbating synovial inflammation and disease development (Fang et al. 2019). The pathogenesis of RA is illustrated in Fig. 2.

Figure. 2.

The figure illustrates the complex network of cell subgroups and cell mediators involved in the development of rheumatoid arthritis (RA). It shows the interaction between various cells and mediators that promote bone destruction, angiogenesis, and synovial inflammation. The figure also highlights the different pathways and molecules involved in the inflammatory and anti-inflammatory processes in RA. Overall, the figure provides a visual representation of the heterogeneity of RA and the intricate mechanisms underlying the disease. Inflammation the synovial site has been arises due to various factors such as upregulation of monocytes, neutrophils, osteoclast and polarization of M2 macrophage (anti-inflammatory) into M1 macrophage (pro-inflammatory). These all factors contributes towards the up-regulation of pro-inflammatory cytokines such as IL interleukins, MMPs matrix metalloproteinase, CCL CC chemokine ligand, VEGF vascular endothelial growth factor, receptor activator of nuclear factor kappa beta (NFkB) ligand (RANKL) and stands for PGE Prostaglandin

Current treatment strategies for rheumatoid arthritis

Curing RA remains out of our reach, and the acceptance of immunologic resistance will not be accomplished until the auto-antigens or cytokine cascades in RA have been completely recognized. A wide range of anti-rheumatic drugs are accessible to diminish painful symptoms and to moderate down disease progression. Current therapy of RA is associated with the suppression of disease progression, relief from joint inflammation, and pain that prevents joint and articular sub-structure damage. The primary goal of present treatment is to diminish bone erosion and restoration of joint mobility, and overall joint function but still, they cause RA remission (Bullock et al. 2019). Generally, current therapy of RA is subdivided into three major classes: (1) non-steroidal anti-inflammatory medicines (NSAIDs), (2) corticosteroids (3) and disease-modifying anti-rheumatic therapies (DMARDs) (Table 1). This medication solely provides symptomatic relief for RA. Although the conventional therapeutic agents show their effects to some extent, long-term usage or dose escalation can result in life-threatening side effects that occurs due to accumulation in non-target organs, tissues, cells, and subcellular domains like protein loss, non-target delivery, stomach upset, nephrotoxicity, the immune-suppression effect that reduces patient consistency (Gokhale et al. 2019). The numerous traditional dosages available for RA includes tablets, capsules, topical dosage form, oral liquids, parenteral, and transdermal patches. The predominant drawbacks related to the traditional dosage forms were shorter half-life, lower patient compliance, low bioavailability and solubility which can be stepped forward with the aid of using nanoparticles. As a result, patients are in desperate need of innovative techniques with low systemic toxicity, high specificity, and better treatment results.

Table 1.

Drugs used in rheumatoid Arthritis

Sr. No	Category	Examples	Mode of action	Side effects	Reference
	Glucocorticoids	Prednisone, Prednisolone, Budesonide, Methylprednisolone, Triamcinolone, Cortisol (hydrocortisone), Dexamethasone, Betamethasone	Lipocortins are phospholipase A2 inhibitory proteins that are stimulated. Lipocortins inhibited arachidonic acid release and regulated the formation of prostaglandins and leukotrienes	Blurred vision, tingling, cushingoid appearance, Osteoporosis, glaucoma, diabetes	(Costello et al. 2020)
	Non- steroid inflammatory drug (NSAID)	Ibuprofen, Piroxicam, Naproxen, Nabumetone, Diclofenac, Etodolac, Rofecoxib, Celecoxib, Valdecoxib, Famotidine	Inhibits prostaglandin production by inhibiting cyclooxygenase; controls glomerular filtration, renal salt, and water excretion	Dyspepsia, nervousness, indigestion,, nausea, vomiting, pneumonitis, anorexia, occult blood in stool, flatulence	(Vaishnavi et al. 2017)
	Disease-modifying anti-rheumatic drugs (DMARDs)	Sulfasalazine, Leflunomide, Tofacitinib, Methotrexate, Hydroxychloroquine	Blocked Prostaglandin and leukotriene synthesis; bacterial peptide-induced neutrophil chemotaxis was decreased; adenosine-induced secretion was reduced;	Anemia, carcinogenic potential, convulsions, Visual disturbance, Mouth ulcers, hair thinning, cardiovascular collapse,	(Benjamin et al. 2019)
	Immunosuppressant	Cyclosporine, Azathioprine	Inhibits the function of the calcium-calmodulin- calcineurin composite phosphatase; promotes NFAT translocation and the generation of NFAT-dependent cytokines	Hypertrichosis, Blood pressure, gingival hyperplasia, dark urine, jaundice, Night sweats, loss of appetite	(Pal et al. 2019)
	Biologics	Infliximab, Adalimumab, Certolizumab, Natalizumab, Rituximab, Canakinumab, Tocilizumab, Etanercept, Abatacept, Anakinra	eliminate the action of TNF-α	Cough, Urinary tract infection, heart failure, puffiness around the eyes, face, lips, or tongue, shortness of breath, back pain, skin rash	(Roszkowski and Ciechomska 2021)
	Enzymes	Superoxide Dismutase, Catalase, Glutathione peroxidase	Replaces an enzyme that is lacking or deficient in the body	Fever, rash, were rigors, flushing, headache, pyrexia, digestive manifestations, myalgia, arthralgia and itching	(Srivastava et al. 2017c)
	Hormones	Estrogen, Raloxifen, Teriparatid	Bind to precise receptors, such as estrogen receptors, which in turn stimulate transcriptional processes and signaling events that upshot in managing gene expression	Genito-urinary symptoms, vaginal dryness, enhance the threat of cardiovascular disease (heart and blood vessel problems) and breast cancer	(Kronenberg 2016)
	Genetic Therapy	Encoding secreted gene products, siRNA, miRNA and genes,	they replace or manipulate defective genes with healthy ones in order to treat genetic disorders	cancer, unwanted immune system reaction, allergic reactions, or damage to organs or tissues	(Presta et al. 2005)

Nanoparticles for the treatment of rheumatoid arthritis

The common underlying cause of musculoskeletal illnesses is not a single particular component or problem associated with a biochemical pathway. Instead, cartilage and bone disorders are multifaceted, involving a wide range of variables and metabolic processes. These complicated variables necessitate a more detailed investigation. The systemic administration of medications in polyarticular degenerative joint diseases is limited by the inability to distribute sufficient dosages to the desired areas and the danger of systemic toxicity. The most typical treatment technique in di-arthrodial joints, such as the knee joint, is intra-articular injection, which creates a high concentration of the medication near the more superficial layers of cartilage while also reducing the overall dosage at the targeted site. While local administration of the medication at the di-arthrodial joint enhances bioavailability, it has the drawbacks of rapid removal from the synovial cavity and limited cartilage penetration. In addition to the danger of infection, frequent injections into the joint cause patient pain (Bhoi et al. 2024). Furthermore, due to the phagocytic activity of macrophages inside the synovial cavity, off-target builds up of the medication results in its clearance from the lymphatic channel. As a result, just a trace amount of the medication stays in the cartilage tissue (Rabiei et al. 2021).

Physical and electrical barriers in the extracellular matrix (ECM), as well as avascularity, limit medication absorption in the cartilage even more. Notably, the existence of a thick collagen II network and aggrecan's negative electrical charge are features that impede penetration of the therapeutic agent into the cartilage matrix (Rabiei et al. 2021).

The advent of nanotechnology has assisted in the resolution of difficulties in medication delivery to bone and cartilage. Nanomaterials' beneficial qualities, such as their tiny size, high retention capacity, and low sensitivity to phagocytosis, have improved patient compliance for bone disorders. Nanotechnology was concerned with the ultra-small structures having dimensions ranging from 10^–9 to 10^–7 m. It also studies nanoscale structures, materials, and components with novel and remarkable physical, synthetic, and biological characteristics. It is one of the most widely used translational medicine technology. The ability to target NPs allows them to adhere to certain cells such as chondrocytes and inflammatory agents. NPs intended for medication delivery must be positively charged in order to connect to the negatively charged cartilage and prevent filtering via the cartilage's pores. In addition, nanoparticles provide the targeted delivery of drugs with minimal drug loss and assess the treatments' in vivo viability. Nanotechnology enhances the safety profile of drugs with high toxicity, and these nanoforms act directly and passively to the target tissue (Yadav et al. 2020, 2022).

Angiogenesis in RA is characterised by restricted fenestration of blood capillaries, making passive delivery inefficient. As a result, active distribution via a targeted agent is favoured. By delivering a greater dose of chemical pathway inhibitors to the arthritic joints and causing a decrease in drug clearance by macrophages, a targeted nanocarrier permits a more stable supply of the medication to be present in the ECM of cartilage. Lymphatic leakage causes the enhanced permeability and retention (EPR) effect in RA, which is characterised by fenestrated capillaries. Because of RA’s poor angiogenesis, the vasculatures have many fenestrations, allowing for passive administration of nanodrugs. Nanodrugs with dimensions less than 200 nm can be used to treat RA because they can pass through fenestrated capillaries. Additionally, covering the NPs with hydrophilic polymers hinders the nanodrug's quick breakdown and rapid renal clearance, allowing the drug to accumulate at the arthritic joints. Attraction of inflammatory macrophages and suppression of lymphocyte proliferation are two broad objectives sought by the use of nanodrugs in the treatment of RA. Thus, macrophage and lymphocyte surface indicators are helpful in the targeting of NPs (Rabiei et al. 2021).

Metallic nanoparticles

Since ancient times, metals have been used in numerous equipment and weaponry for animal chase and agricultural activities. Following that, people began to investigate the numerous applications of metals in various fields, including hardware, structures, electronics, coatings, autos, and finally, biology and medicine. Surprisingly, few metals present in living organisms are critical for the human body’s optimal functioning. Zinc, for instance, is necessary for proper growth, metabolism, immunology, wound healing, and neurological and enzymatic responses, among other biological activities (Slama 2015). Calcium and Magnesium are required for adenosine triphosphate (ATP) (the body's principal energy source) to work correctly during metabolism. Calcium is also essential for signaling, bone regeneration, muscular function, and cell wall formation (Hemon et al. 2017). Manganese participates in various redox processes in living organisms, including photosynthesis in plants. Heme, which includes iron, is a cofactor in hemoglobin and is essential for oxygen delivery in all vertebrates’ blood (Wallace 2016). Iron is also found in metalloproteins such as cytochrome P450, xanthine oxidase, and monooxygenase. Copper is essential in hemocyanin, which delivers oxygen to the blood of arthropods and molluscs. Scientists have also made tremendous progress in understanding how these various metals function in biological systems since the mid-1980s. Even though specific metals/metal ions have extensive biological interactions in living organisms but when administered externally for diagnostic or therapeutic reasons, they can demonstrate more significant degrees of cytotoxicity. According to several sources, these metal nanoparticulates (nanoparticles, nanorods, and nanospheres) can be employed for in vivo therapeutic applications due to their extraordinary and exceptional biological and physicochemical characteristics compared with bulk forms of similar metals (Grumezescu 2016). Metal nanoparticles have been widely employed in bioscience and medicine because of their size similar to cells, higher interaction with nucleic acids, receptors, and proteins. In addition, multiple investigations have revealed that metal nanoparticles may be removed by urine and faeces, confirming their biodegradability. From the past few decades, researchers have been excessively preoccupied with numerous research projects for the development of alternative diagnostic and therapeutic nanomedicine strategies for the treatment of various disorders (e.g., diabetes, cancer, rheumatoid arthritis, ischemic ailments, and neurodegenerative disorders) using metal nanoparticles (Thota and Crans 2018; Bera and Kumar 2022).

Synthesis of metallic nanoparticles

The two basic approaches for making nanoparticles are “Top-down” and “bottom-up.” The term “top-down” refers to the milling method used to crush raw material mechanically. The top-down method comprises repeated quenching, lithography, and milling, while the bottom-up method comprises the molecule by molecule method, cluster-by-cluster, and atom by atom method. Nanotechnology involves understanding the characteristic physical phenomena of nanostructure and nanomaterial. The chemical constitution of the nanoparticles and the required features for the nanoparticles determine the formulation process. Precipitation reactions, sol–gel processes, and aerosol processes are all part of it. Bottom-up techniques rely on subatomic or molecule self-physical association's properties (Cele 2020).

This approach yields preferable and puzzling structures from molecules or atoms, with more control over their sizes and forms (Cele 2020). Various physical, chemical, and organic methods are available to obtain desired size and shape, surface functionalization, morphologies, and maximum product production with limited formulation components. In order to obtain such desirable nanosize particles and other properties, defined production and response conditions are necessary. Temperature, chemical composition, pH, surface modifications, and process controls particles' size, composition, shape, and crystallinity. The most significant advantages of physical procedures over chemical strategies are the lack of solvent contamination, toxic and perilous components, chemicals inside the manufactured thin films, and the regularity of nanoparticle dispersion. In general, each of them (chemical, ultrasonic-assisted, electrochemical, photocatalytic, photoinduced, biochemical reduction, and irradiation techniques) has its own set of constraints, including toxicity, cost-effectiveness, and laboriousness, among other things (Yadav et al. 2022). The various methods used for synthesis of metallic nanoparticles are shown in Fig. 3.

Fig. 3.

Synthesis of Metallic Nanoparticles: Metallic nanoparticles has been synthesised via two different methods i.e. Top-down method and bottom up method. Further, Top-down method has been sub-divided into Physical mehod while bottom up method sub-divided into Chemical method and Bio-reduction method

Characteristics of metallic nanoparticles

Ideal nanoparticle-based pharmaceutical delivery system depends on the response of the body towards external particulate matter. Infusion, inhalation, and oral intake are the three main mechanisms used by nanoparticles to enter the human body. Biological protein and particle interaction is the basic process that occurs when they enter the systemic circulation before being distributed to various organs (Mu 2017). Absorption from the blood vessels allows the lymphatic system to transport and eliminate the particles. This system has three basic capabilities, two of which are connected to medication delivery. The first fluid recovery is the exudation of blood vessels via the lymphatic network. The second, dealing with immunity, is possibly the most pertinent to this discussion. As the system removes excess fluid from tissues, it also removes chemical and external cells. As the fluids are filtered back into the circulation, the lymph nodes detect any foreign substances passing through (Park et al. 2016). Metallic nanoparticles have a plethora of characteristics that render them uniquely advantageous for RA treatment. For starters, their compact size allows for a high surface area-to-volume ratio, which improves drug loading and delivery to specific areas while reducing systemic toxicity. Furthermore, metallic nanoparticles have natural anti-inflammatory capabilities due to their ability to scavenge reactive oxygen species and control cytokine expression, which reduces the inflammatory response associated with RA (Bhoi et al. 2024). Furthermore, their tuneable surface chemistry can be modified to allow for selective binding to inflamed tissues, resulting in precise drug administration and therapeutic efficacy (Yang et al. 2021). Apart from biological properties supported by metal nanoparticles, their basic characteristics support numerous processes.

Metal-based nanomaterials, are expected to revolutionize many aspects of our life, including technology, biology, and industry (Ramos et al. 2017). Metal nanoparticles possess a wide range of qualities that are pretty beneficial or may be monitored for a wide range of new logical as well as biological and mechanical applications. When compared to mass counterparts, MNPs have distinguishing characteristics such as high energies at the surface, a massive number of low coordination spots, such as edges and corners, with countless “slewing connections” and thus specific and chemical features, and the ability to store an abundance of electrons; Plasmon excitation. Furthermore, the transition between molecule and metallic states produces a distinct electronic structure (regional density of states, LDOS), magnified crimps, minute extension ordering, and atomic captivity. The form, size, crystallinity, surface structure, and phase of nanomaterials determine features that are known to be constant for bulk materials. The form and size of metal nanoparticles are the two key parameters determining most of their characteristics. If one of the MNPs is larger than the other or varying in shape, it means they have drastic differences in shading, electrical conductivity, and melting temperatures (Ramos et al. 2017).

Furthermore, metallic nanoparticles are very biocompatible and stable, allowing for prolonged circulation in the bloodstream and sustained release of therapeutic chemicals (Yadav et al. 2022). Overall, the multiple features of metallic nanoparticles show tremendous promise for revolutionising RA treatment.

Nanoparticle–cell interactions and cellular uptake of NPs

Any malfunction, hormonal imbalance, internal injury, infection in the body, or external factors (such as foreign particles or microbes) leads to inflammation. Inflammation also occurs due to food sensitivity, obesity, and environmental toxicity. There are two kinds of immune response present in the cell, i.e., innate immunity and hormonal immunity. Innate immune cells consist of antigen receptors. Antigen receptors detect any chemical signals generated from infected cells and infectious agents, and accordingly, they mediate their response. During the inflammatory process, if any imbalance occurs in regulatory signals, it promotes tissue and cellular damage (Brenner and Krakauer 2005). Damaged cells or tissue or infectious tissue generate their response; a pattern of damage causes recruitment of stem cells, killer cells, and macrophages that deal with the response (Bianchi and Manfredi 2014; Wynn and Vannella 2016). Macrophages play a crucial role in regulating the inflammation process. It is a mononucleotide, macromolecule; heterogeneous phagocytic cell produced in the bone marrow and is mobile as monocytes in the systemic circulation (Agarwal et al. 2019). From the generation site, monocytes drift towards the infectious site in various tissues. There are two kinds of macrophages in our bloodstream, i.e., M1 and M2 macrophages. M1 macrophages are pro-inflammatory macrophages that promote inflammation, while M2 macrophages mediate anti-inflammatory action. By controlling transformation between M1and M2 macrophages. Macrophages initiate, maintain, and regulate various inflammatory processes in the cell (Tardito et al. 2019). During the inflammation process, macrophages engulf debris of cells and tissue by phagocytosis and activate signals that promote inflammation and activate macrophages. Activation of signals involves lipopolysaccharide (LPS), cytokines, and extracellular matrix proteins (Fujiwara and Kobayashi 2005). In response to inflammation, neutrophils migrate towards the inflammation site and release pro-inflammatory mediators at the macrophages site. Further various types of cellular interactions and its uptake by cells are demonstrated in Fig. 4.

Fig. 4.

Cellular uptake of metallic nanoparticles: (a) cellular uptake of metallic nanoparticles (MNPs) depend upon its size, shape, surface charge:—endocytosis mediated via Clathrin, Receptor and Caveolin, formation of protein corona, Pinocytosis and direct penetration (b) When MNPs enter within the cell, they are held within protein corona, endosomes and vesicular compartments, which can have interior or exterior receptors. To accomplish functional delivery, most MNPs must escape from these compartments before they acidify. Thus, MNPs entrapped in the protein corona act as ligand for macrophage receptor and after binding to it, MNPs get released while MNPs within the neutrophils molecules get release through NETosis mechanism. The responsive NPs, such as ionizable MNPs that become charged in low-pH conditions, aid in endosomal escape and intracellular delivery, whereas unresponsive NPs frequently remain stuck and are destroyed by lysosome acidity and proteolytic enzymes

Formation of protein corona by metal nanoparticles

There are various routes through which Metallic NPs enter the body, like dermal, oral, and nasal routes. As nanoparticles have a more diminutive size, they can easily cross biological barriers such as mucous linings, sense organs, and systemic circulation. In the systemic circulation, metallic NPs bind the protein. This binding promotes protein corona formation around the NPS like immunoglobulin (IgG), fibrinogen, and immunoglobulin M (IgM), which promote inflammatory reaction. The composition, formation, and binding pattern of NPs with Protein corona depends on the physicochemical property such as size, surface charge, geometric shape, and chemical composition. Serum proteins are less abundant in the circulatory system, but they have a high affinity towards metallic NPs. Thus, serum proteins have a crucial role in forming protein corona that modifies the external structure of nanoparticles and provides biological identity to NPs. The biological identities help determine the interaction and transportation of NPS at different chemical responses (Agarwal et al. 2019).

Ionic channel

The pores and ion channels in the cell membrane provide important route for NPs entry, which depend upon the nanoparticle size. Uptake of NPs by cells carried out without any membrane receptor involves various adhesive interactions such as steric interaction, electrostatic interaction. Size of NPs also triggers different localization effects on cell (Simkó et al. 2011). For example smaller metallic NPs at elevated concentration are readily engulfed by cellular vesicles. Most of engulfing by macrophages and neutrophils are carried out by macro-pinocytosis and Phagocytosis. At inflammatory site, whenever the protein coated metallic NPs come in contact with surface receptors of macrophages or neutrophils it form protein corona around the NPs (Agarwal et al. 2019). Serum proteins are vastly present in the protein corona that act as a ligand for M2 macrophage receptors and activate anti-inflammatory M2 macrophage. Activation of M2 macrophage initiate NP uptake. This demonstrates that occurrence of serum proteins; enhance the uptake of NPs by M2 macrophage as compared to M1 macrophage. Array of phagocytosis gene study conducted in between M1 and M2 cells exemplify an amazing enhancement in expression of complement factor and immunoglobins receptor in M2 macrophage in contrast to M1 macrophage. It supports that serum protein adsorption plays a crucial role in NPs uptake via a M2 macrophage (Binnemars-Postma et al. 2016).

NETosis

Metallic nanoparticles also penetrate into cell via NETosis mechanism. In NETosis, an extracellular traps (NETs) grow around neutrophils in response to endogenous stimuli such as uric acid or cholesterol, as well as external stimuli such as pathogenic microorganisms or foreign particles. Mitosis is the process by which these NETs develop and is impacted by interaction with pathogenic bacteria or fungus as well as inflammatory stimuli. NET production is influenced by receptor-interacting protein kinase 3 (RIPK-3) enzymes and reactive oxygen species (ROS) radicals (Srivastava et al. 2017c). ROS are extremely unstable and reactive due to the presence of unpaired electrons in their outermost shells. They are generated as a result of lipid peroxide production, which causes membrane damage. This increases the surface area of the cell membrane, causing more O2 absorption on the surface and, as a result, greater ROS generation (Agarwal et al. 2019).

Metallic nanoparticle-mediated anti-rheumatoid activity

Metallic nanoparticles (MNPs) are unique in modulating the immunological and anti-oxidant activity, which synergize the anti-arthritic therapies. By converting the hypoxial environment into normoxic condition, MNPs inhibit expression of HIF 1, which is responsible for therapeutical failure and multi-drug resistance. Not only these, MNPs mediate duplication of GSH, ROS and nitric oxide synthase (iNOS) generation, and allow more easily accessible RA therapies. MNPs mediated anti-arthritis activity hinders proliferation of mast cell, blocking the release of pro-inflammatory cytokines, and prostaglandin E2 (PG-E2). It is reported that the MPs altered the type of immune cell, such as repolarisation of pro-inflammatory macrophage (M1) into anti-inflammatory macrophage (M2), activation of selenoenzymes (such as GPxs and TrxRs), and modulating the various pathways (MAPK and PI3K pathways). MNPs act via multiple therapeutical modes which are discussed below (Zhang et al. 2016).

Reduction of ROS production (oxygen radical scavenging)

For many years, it was considered that oxidative stress is the major cause of inflammatory disorder like RA. The oxidative stress arises due to imbalance between free radicals and defensive anti-oxidant system. There has been a numerous evidence pointing to the significance of reactive nitrogen and oxygen species in RA development (Kirdaite et al. 2019). ROS affects the extracellular matrix and cartilage by inhibiting the formation of proteoglycan and collagen. ROS and other free radicals have a role in RA inflammation via a variety of mechanisms, including nitrous oxide in vascular tone control, hydrogen peroxide in cytokine transcription (TNF- and IL-2) and superoxide in fibroblast proliferation. During inflammation, phagocytes initiate a cascade of unrestrained release of free radical, which damages biomolecules and causes inflammation. Oxidation modified low density lipoproteins inactivate inhibitor of protease-1, lipid peroxidation, and damage DNA. According to different research, the basis to RA pathogenesis is a weakened antioxidant defence system and increased oxidative stress (Qamar et al. 2021).

ROS is a kind of lipid peroxidation-inducing agent that implicated in deterioration of cartilage and inflammatory arthritis (Kirdaite et al. 2019). ROS are oxygen metabolites that have been partially reduced and have strong oxidising properties. ROS are produced as a by-product of NADPH oxidase and the Electron Transport Chain (ETC). ROS damages DNA by oxidising proteins and lipids within the cell. Not only have these ROS oxidized tyrosine phosphates promoted dysfunction of endothelial and cellular damage. Superoxide anions in combination with nitrogen oxidase limit the rate of diffusion and result in the production of reactive nitrogen species (RNS). In phagocytosis, RNS promotes nitrosative stress that leads to the production of ROS. ROS generation is an endogenous mechanism in which cytochrome oxidase accepts electrons from membrane carriers to produce superoxide ions. The intracellular GSH, on the other hand, scavenges the ROS, sustaining equilibrium. The lowered amount of antioxidant enzymatic activity of glutathione peroxidase (GPX), catalase, and super oxide dismutase (SOD) in RA exacerbates the ROS. The ROS system reduces chondrocyte cell activity in the formation of matrix components by decreasing the response to growth factors, which in turn limits the synthesis of proteoglycans and disturbs the binding of proteoglycans to hyaluronans. Radicals also contribute to the cross-linking of collagens and the degradation of chondroitin sulphate. The ROS system activates NF-B by eliminating its inhibitory factor-B, which directs the factor's binding to DNA. The activation of transduction signaling provokes expression of cytokines, Proinflammatory genes, adhesion molecules, chemokines, and proteases. As a result, ROS increases angiogenesis and inflammation while also maintaining the arthritic state. Increased ROS levels activate p65, TGF, and tumour necrosis factor-alpha. In brief, increased ROS production causes the release of IL-1, IL-8, IL-6, CXCL-12, TNF, NOX2, COX-2, and IL-2 (Srivastava et al. 2017a).

Metallic nanoparticles are potential antioxidants and effective tools in quenching ROS, including H₂O₂ and the superoxide anion radical in a dose-dependent manner. In 2019, Kirdaite et al. processed the gold nanoparticles (Au NPs) to evaluate their ability to suppress ROS. Kirdaite (Kirdaite et al. 2019) reported that Au NPs of 13 nm and 50 nm reduced malondialdehyde (MDA) generation while dramatically enhancing CAT activity, responsible for the direct removal of ROS. This doesn’t cause any adverse effect on hematological indices and suppresses cartilage erosion, synovial angiogenesis, and joint swelling in the earlier stage of arthritis. Similarly, Baldim et al. 2018, demonstrate that cerium oxide nanoparticles (CeO NPs) can reduce ROS level, which is size and shape-dependent. Both in vitro and in vivo results show that CeO NPs having 2 to 20 nm eventually distribute over the more extensive verities of cell line and serum where it suppresses superoxide radicals, H₂O₂, OH•, and NO that diminish ROS level in the serum (Baldim et al. 2018).

Inhibition of iNOS expression

NO is a free radical cell signaling molecule that plays an essential role in the pathophysiology of various inflammatory disorders. NO has a half-life of around 3–6 s and may readily diffuse through cell membranes. Nitric oxide synthase (NOS) enzyme synthesizes NO via Calcium ions and NADPH as cofactor and arginine and oxygen as substrates (Abramson et al. 2001). In addition to these, the Inducible nitric oxide synthases (iNOS) promote a higher release of NO, which is highly toxic to the cell. Previous research suggests that NO has a role in controlling inflammatory activities such as transmigration and transcription of pro-inflammatory genes, leukocyte rolling, and vascular response modulation. NO regulates the function of the host immune cell that regulates specific immunity. Along with these, it causes damage to local tissue and promotes inflammation. NO inhibits leukocyte rolling and transmigration by lowering adhesion molecules (VCAM & ICAM) expression (Agarwal and Shanmugam 2019).

NO is also involved in the phagocytosis of the invading microorganism. The phagolysosome membrane produces NO and hydrogen peroxide, and other oxygen derivatives. They aid the organism to phagocytose by inactivating key enzymes and acting as cytotoxic agents (Tripathi et al. 2007). NO is cytotoxic to the microbe and the cell that produces it and other nearby cells, damage the host tissue. NO has a function in controlling specific immunity by causing host immune cells to die at excessive concentrations. In addition to being cytotoxic, NO can form complexes with superoxide radicals, resulting in reactive oxidants that can harm both target and host cell. Lipopolysaccharide (LPS) is a potent suppressor of NOS expression and, as a result, a vital regulator of NO generation. Within the other host cell, the elevated level of NO induces a toxic chemical reaction. Combining LPS and Interferon-γ (IFN-γ) significantly boost iNOS expression. The use of gold nanoparticles in the therapy of RA has also been studied, with encouraging results. In this regard, Gul et al. investigated the use of gold nanoparticles in the treatment of RA. By manipulating the expression of NF-kB and iNOS, they evaluated the immunomodulation potential of rutin and rutin-conjugated gold nanoparticles (R-AuNPs) in the collagen-induced arthritis (CIA) model of rats. In the CIA model of rats, rutin and R-AuNPs displayed anti-arthritic effects, as evidenced by a considerable decrease in an arthritic score and a significant reduction of iNOS and NF-kB expression in vivo (Gul et al. 2018). In conclusion, rutin and R-AuNPs have been identified as possible therapeutic agents for the treatment of RA by suppressing the NOs production. In a dose-dependent manner, ZnO NPs have been found to lower LPS-induced NOS mRNA and protein expression levels. Interferon (IFN), a pro-inflammatory cytokine, is a potent macrophage activator and inducer of MHC Class II expression. According to the literature, 10 g/mL ZnO NPs suppress NO generation in (RAbbit Wistar) RAW 264.7 macrophages induced by a combination of IFN- and LPS. Inducible NOS protein expression levels have also been shown to be inhibited by ZnO NPs (Suschek et al. 2004; Tripathi et al. 2007; Agarwal et al. 2019).

Anum Gul et al.’s work aims to determine the function of bioflavonoids, rutin, and rutin-conjugated gold nanoparticles (R-AuNPs) in the regulation of NF-κB and iNOS expression in the CIA model in order to evaluate their anti-arthritic mechanism. The subcutaneous injection of bovine type II collagen resulted in arthritis. By taking the arthritic score every other day until a mean score of 4 was recorded, the severity of the arthritis was ascertained. Serum samples were also examined for the presence of PO and NO. iNOS and NF-κB expression levels were assessed using immunohistochemistry and real-time RT-PCR on spleen tissue samples. The treated groups showed a noticeably lower arthritis score as well as NO and PO levels. In comparison to the arthritic control group, there was a notable downregulation of NF-κB and iNOS expression levels in the therapy groups. The results point to rutin and R-AuNPs having a possible therapeutic function in the management of rheumatoid arthritis.

Down-regulate (HIF)-1α expression

The influx of macrophages and leukocytes into the synovial capsule, followed by matrix breakdown by the matrix metalloproteinase enzyme, characterizes inflammation of the synovial membrane and connective tissue in RA. Monocytes and phagocytes penetrate the matrix, degrading it and producing reactive superoxide radicals, hydrogen peroxide, and reactive hydroxyl radicals. Because of the overexpression of VEGF, arthritis is exacerbated by neovascularization. As a result, this neovascular system distributes oxygen to increased inflammatory cells but fails to meet the oxygen demand, resulting in hypoxia. Reoxygenation occurs as a result of the hypoxic state. Due to homeostasis failure caused by joint degradation and the creation of reactive oxidants that contribute to tissue damage, the alternate cycle of both causes persistent oxidative stress in the surrounding environment (Liang et al. 2010). Hypoxia and inflammatory factors such as cytokines, interleukin-1 (IL-1), high temperature, low pH, TNF-, growth factors [epidermal growth factor, fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, insulin-like growth factor-I and -II, platelet-derived growth factor-BB (PDGF-BB), and heregulin], reactive oxidants, and nitrogen species all-cause HIF-1 transactivation activity. Hypoxia-Inducible Factor (HIF)-1 expression is reduced by Ag nanoparticles. (HIF)-1 regulates pro-inflammatory gene expression and facilitates bacterial death. It also improves neutrophil survival in anaerobic or low-oxygen environments (Agarwal et al. 2019). Less O2 causes an increase in TNF, IL-1, and IL-6 levels in macrophages and Kupffer cells. Inflammation-related adipokines are observed in greater concentrations in hypoxic tissues (Lin and Simon 2016). HIF-1 binds to the HRE (Hypoxia Response Element) DNA sequence and triggers transcription of pro-inflammatory genes in the target. Ag NPs suppress the activation of target genes by decreasing the activity of the HRE reporter generated by HIF-1 in human breast cancer cell lines. They also suppress HIF-1 protein production and the activation of endogenous HIF-1 target genes such as GLUT1 and VEGF-A (Yang et al. 2016a).

In order to control hypoxic reactions in RA, the HIF signalling must be activated. The p53 reacts to a range of stress signals, including hypoxia, and selectively transcribes its target genes to control different cellular reactions in order to regulate its oxidative level in RA. Studies have shown that the p53 signalling system and hypoxia interact closely but intricately. Depending on the cell/tissue type, the degree and duration of hypoxia, and the HIF signalling, the p53 levels and activities can be controlled in many ways. Ruijiang Liu and co-worker demonstrate that the modified Iron NPs (Fe₃O₄/-Fe₂O₃/CA-PEG-celastrol) increased cell death by encouraging the production of intracellular ROS. As a result, more HIF-1 was produced, which inhibited the growth of p53 when paired with MDM2 protein. As a result, apoptosis was promoted, Bax and caspase-3 expression were elevated, Bcl-2 expression was lowered, and the p53-driven apoptosis pathway was activated. The ROS scavenger NAC reduced ROS expression, which in turn reduced HIF-1 expression. At the same time, p53, the Bax/Bcl-2 ratio, and caspase-3 were all down-regulated.

Impedes mast cell proliferation

ZnO NPs act as anti-inflammatory agent in numerous ways. In response to various microbial activities, internal or external injuries, the epithelial cells release thymic stromal lymphopoietin (TSLP). TSLP enhances synthesis of IL-13, growth factors for mast cell, thus, proliferate mast cell. From different report, it has been shown that TSLP also enhances production of IL-1 and TH2 cytokines (Kim et al. 2016). In an activated form, mast cell produce inflammatory mediator such as histamine, metabolites of arachidonic acid which act on inflammatory cytokines and mucous gland (Amin 2012). ZnO NPs successively suppress TSLP that ultimately suppress all inflammatory activity of TSLP. ZnO NPs regulate p53 protein level which suppresses mast cell proliferation and enhances release of High-Mobility Group Protein 1 (HMG-1) that promotes pro-tumorigenic inflammation. HMG-1 induces production of chemotaxis and cytokines (Yan et al. 2013; Magna and Pisetsky 2014).

Activation of selenoenzymes (GPxs and TrxRs)

There are thirty seleno-proteins identified in mammals and 25 seleno-proteins are found in humans but only some of them have been functionally characterized like glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs), selenoprotein P (SePP), the selenophosphate synthase2 (SPS2), iodothyronin deiodinases, among others (Ali et al. 2017). The seleno-enzyme family (GPx-GPx1, GPx4, GPx3, GPx6, and GPX5) has significant antioxidant activity and is involved in cell defence against oxidative stress caused by ROS and RNS like superoxide, hydrogen peroxide, hydroxyl radicals, peroxynitrite and nitric oxide (Holmes et al. 2009). Selenium is a cofactor of selenoenzymes like TrxRs and GPxs, and it may have an anti-inflammatory effect by inhibiting the NF-kB cascade, reduces release of inflammatory mediators, or hinders signalling pathways of immune cell, predominantly in macrophages. Ali et al. studied the role of selenoproteins such as SePPs and GPxs, as well as other selenoproteins found in the blood. RA patients' synovial fluid, erythrocytes, plasma, and leukocytes all had low levels of Se (Ali et al. 2017). Similar results has been determine by Agarwal et al., where the level of Se is lower in their plasma, and levels of C-reactive protein (CRP), interleukin-6 (IL6), and adhesion molecules such as E-selectin and VCAM had increased in RA patients as compared with controlled group (Agarwal et al. 2019).

Blocking pro-inflammatory cytokines

Pro-inflammatory cytokines are responsible for the overexpression inflammatory responses and leads to inflammation. They also proliferate and differentiate mast cell. Mast cells are well known for their important role in regulation of immunity in immune disorder by liberating different inflammatory mediator such as cytokines, leukotrines, chemokines and histamine. Along with these, it induces synthesis of IgE and promotes allergic inflammatory response (Amin 2012). Activated form of NF-κB altered the expression of certain genes that effect proliferation of cell, thereby, increase the inflammatory reaction (Simmonds and Foxwell 2008). The caspase-1 enzyme is kind of IL-1β converting enzyme which activates cytokines like pro-IL-18, IL-1β. ZnO NP has tendency to block the NF-κB and caspase-1 enzyme in activated mast cell. Some studies also show ZnO NPs upregulate A20 which is a negative regulator of NF-κB in RAW 264.7 macrophages and suppress NF-κB. Along with these, it suppresses NF-κB and p65 nuclear translocation reducing cytosolic degradation of IκBα. This in turn, inhibits transcription of NF- Κb, and production of pro-inflammatory cytokines i.e. IL-1β and TNF-α. Depending upon the dose concentration, ZnO NPs suppress production of malondialdehyde (MDA), an oxidative marker. ZnO NPs diminish the neutrophil activity by downregulating myeloperoxidase levels (Kim et al. 2016). Sumbayev et al. investigated the therapeutic potential of gold nanoparticles stabilized by citrate in IL-1-dependent inflammatory diseases like psoriasis. The AuNPs specifically downregulate cellular responses produced by IL-1, according to in vitro and in vivo experiments. They also suggested that citrate-stabilized gold nanoparticles might be a viable novel psoriasis therapy. Both these findings imply that AuNPs can be used to make medications and heal autoimmune diseases (Sumbayev et al. 2013).

Inhibit release of pro-inflammatory cytokine

Persistent synovitis, caused by an influx of immune cells into the joints, is one of the characteristics of RA. These cause the release of T cell, B cell, and other innate effector cells, establishing a complex network that encourages the production of pro-inflammatory cytokines. Pro-inflammatory cytokines activate fibroblast-like synoviocytes that degrade bone and cartilage. The release of pro-inflammatory cytokines is also mediated by innate immune cells such as macrophages, neutrophils, and mast cells. In RA, macrophages M2 polarise into a pro-inflammatory ‘M1’ macrophage, resulting in the production of pro-inflammatory mediators and a decrease in regulatory and anti-inflammatory cytokines such as TGF, IL-4, IL-13, and IL-10. However, the morphologies of synovial macrophages in RA patients are heterogeneous and do not adhere to a rigid M1 or anti-inflammatory ‘M2’ pattern (Chen et al. 2019). Silver has anti-inflammatory properties as it decreases vascular endothelial growth factor (VEGF) and inhibits the polarisation of inflammatory macrophages. According to these, antigen response stimulates the epithelial cell to produce VEGF (Srivastava et al. 2017b). Further, VEGF causes physiological dysfunction, plasma proteins leakage in the extravascular site results in thickening of windpipe wall. It also increases type −2 T helper cells and releases pro-inflammatory cytokines such as IL-4, IL-3, IL-9, and IL-13. Higher antigens produce an allergic reaction. Yihua Yang and its co-worker develop folic acid-modified silver nanoparticles (FA-AgNPs), which may actively transport into M1 macrophages and work in concert with one another. To effectively treat RA, M1 macrophages must be reduced and M2 macrophages must be polarised. In the AgNPs, easily made, PEGylated, and modified with FA to achieve M1 macrophages targeting administration through the surface-expressed folate receptor (Yang et al. 2021). The reduction of RA is successfully observed in CIA. By the Src kinase pathway, IL-1β and VEGF promote permeability of endothelial cells through phosphorylation of Src at Y419. Ag NPs tend to block phosphorylation of Y419 and suppress the Src kinase pathway, thereby decreasing the permeability of endothelial cells induced by IL-1β and VEGF. An enhanced vascular permeability is also linked with the upregulation of growth factors and cytokines in the inflammatory region of bowel disease. Ag NPs also reduce cell proliferation by blocking solute flux promoted by IL-1β and VEGF. Not only have these, but another metallic nanoparticle ZnO, Au NPs, Se NPs, and Fe NPs also shows an excellent anti-inflammatory activity by suppressing the expression of inflammatory marker genes like TNF-α, IL-10, IL-6, and IL-1β. By blocking the NF-kB pathway, ZnO NPs change protein release and the production of inflammatory mediators (Agarwal and Shanmugam 2019). LPS enhances the production of pro-inflammatory cytokines. Au NPs are well known for inhibiting the release of inflammatory cytokines such as TNF-α, IL-1β, IL-17 that down regulate epithelial cell proliferation caused by IL-1β. They are also known to decrease from TH1 to TH2 (pro-inflammatory to anti-proinflammatory). Au NPs promisingly inhibit the production of TNF-α and IL-17 promoted by LPS. Au NPs act by reducing the biological activity of IL-1β as IL-1β form aggregates around Au NPs, which are less available for interaction with the IL receptor (Table 2).

Table 2.

Metallic nanoparticles and its mechanism of action for rheumatoid arthritis

Nanoparticle	Inflammation model	Mechanism reported	References
Silver Nanoparticles	Collagen-induced arthritis	Polymerization of M1 (pro-inflammatory) into M2 (anti-inflammatory)	(Yang et al. 2021)
	Freund's complete adjuvant induced arthritis	Inhabit AST, ALT, ALP, LDH and γ-GT enzyme	(Ramaswamy et al. 2019)
	–	suppressed IL-1β and TNF-α release in LPS-stimulated THP1 monocytes and LPS-stimulated or unstimulated TDM respectively	(Yusuf and Casey 2019)
	Freund's adjuvant induced arthritic	Hinder expression of TLR-2 and TLR-4 immune receptors	(Journal et al. 2018)
	Freund's adjuvant induced arthritis	Suppress ROS and RNS	(Dewangan et al. 2017)
	Freund's adjuvant induced arthritis	Inhibited the protein expression of NF-kβ p65 and TNF-α	(Mani et al. 2016)
Selenium Nanoparticles	Collagen type-II induced Grade-4 arthritic mice	Diminish ROS level	(Qamar et al. 2021)
	Collagen-induced arthritic mice	Activation of selenoenzymes	(Qamar et al. 2020)
	Complete Freund’s adjuvant	mRNA expression of antioxidant enzymes such as MnSOD, Cu/ZnSOD, CAT, and GPx1	(Ren et al. 2019)
	Collagen induced arthritis	NO activates autophagy by modulating signalling pathways related to AMPKa and mTOR, increasing the flux of autophagy, inhibiting the activity of NF-kB-p65	(Liu et al. 2018)
	Acute colitis model in mice	Decrease in pro-inflammatory cytokines, protein from colonic inflammation damage	(Zhu et al. 2017)
Zinc Oxide Nanoparticles	RAW 264.7 murine macrophage model	Cytokines like TNF-α, IL-1β, IL-6, and COX-2	(Agarwal and Shanmugam 2019)
Gold Nanoparticles	Collagen-induced arthritis	Inhabit mRNA of TNF-α	(Li et al. 2020)
	Collagen-induced arthritis	Reduces H2O2, superoxide ion radicals, ROS level	(Kirdaite et al. 2019)
	Collagen-induced arthritis	Downregulation in the NF-κB and iNOS	(Gul et al. 2018)
Superparamagnetic iron oxide nanoparticles	Complete Freund’s adjuvant arthritis	Inhabit expression of VCAM-1 and TNF α	(Zhang et al. 2022)
Silver and Gold Nanoparticles	–	Reduces anti-CCP and RF IgM	(Hwang et al. 2020)
	Adjuvant induced arthritis	Suppressed protein and mRNA expressions of TLRs (TLR-2 and TLR-4) and cytokines (IL-1β and TNF-α levels	(Roome et al. 2019)
Aluminum-doped zinc oxide nanoparticles	–	Reduce TSLP and caspase-1 activation in human mast cell line, as well as interleukin (IL)-6, IL-8	(Kim et al. 2016)
Magnesium hydroxide Nanoparticles	–	Inhabit IL-1β, PI3K/Akt and MAPK molecules	(Koga et al. 2023)
Magnesium aluminum layered double hydroxide	–	Suppressions on T helper 17 cell (Th 17)	(Fu et al. 2024)
Manganese oxide nanoparticles	complete Freund’s adjuvant arthritis	Reduce oxidative stress, and modulates polarization of macrophages phenotype from M1 to M2	(Xia et al. 2024)

^{TLRToll like receptors, TDMTHP1 differentiated macrophages, GPxsglutathione peroxidases, COX-2cycloxygenase, ILInterleukins, TNF-αTumor necrosis factor, ASTaspartate transaminase, ALTalanine transaminase, ALPalkaline phosphatase, LDHlactate dehydrogenase, γ-GTgamma glutamyl transferase, TSLPthymic stromal lymphopoietin, VCAM-1Vascular cell adhesion molecule-1}

Modulating MAPK and PI3K pathways in Kuppfer cells and hepatic stellate cells

LPS activates the mitogen-activated protein kinase (MAPK) pathway through a Toll-like receptor (TLR). Phosphatidyl Inositol 3 Kinase (PI3K) pathway regulates cell proliferation, cytokines stimulation, gene expression, and protein synthesis. In human monocytes, the PIP3 pathway decrease production of TNF-α and NF-kβ activation induced by LPS that directly inhibit ROS generation (Zhang et al. 2016). Intracellular, the MAPKS pathway triggers secondary messenger (cyclic AMP and Ca+2) and interaction of G couple cell surface receptor protein. These stimulate of transcription agent that causes alteration of gene expression. Kupper cells are well known to activate and maintain inflammatory response; inactivated state Kupper cells produce a higher amount of cytokines (Yang et al. 2016b). Au NPs were found to be responsible for regulating various signalling pathways, including the PI3K and MAPK pathways, and thus regulating the negative feedback mechanism of pro-inflammatory cytokines in hepatic stellate and Kupper cells, which affects their cytokine profile and oxidative stress.

Increasing thrombin-antithrombin levels

P-Selectin and Cytokines are triggered by thrombin, which downregulates signalling and mediates through protease activated receptors (PAR). Platelet aggregation is mediated by P-selectin in leukocytes (Schabbauer et al. 2004). Prothrombin is released when there is a wound, whether it is internal or exterior, and it is converted into thrombin for blood clotting. Thrombin activates fibrinogen and platelets, both of which are then inactivated by plasma anti-thrombin resulting in TAT (thrombin-antitombin) complex formation. In investigations, Titanium dioxide nanoparticles (TiO2 NPs) have been shown to increase TAT levels, which in turn lower inflammation via the PAR pathway (Agarwal et al. 2019).

Suppressing LPS-induced COX-2 expression

Lipopolysaccharide (LPS) is present in cell wall of Gram-negative bacteria. LPS secretes secondary mediators and pro-inflammatory cytokines via activating macrophages (Srivastava et al. 2018). LPS mediate binding of COX promoter with inducible transcription factor that induces cyclooxygenase 2 (COX-2). LPS induce genetic expression of COX-2, leads to release of prostaglandin E2 (PG-E2) and inflammatory lipids that promote inflammation. Expression of COX -2 is lower in Tumor Progression Locus 2 (Tpl 2) macrophages. ZnO NPs suppress LPS induced COX -2 in macrophage cells and ultimately prevent PG-E2 release (Britt et al. 2012). Ag NPs also suppress release of pro-inflammatory cytokines such as TNF-α and IL-12 and also diminish expression of COX-2 gene at elevated concentrations (Agarwal et al. 2019). Se NPs are known to inhibit the phosphorylation of IκB-α, thus, preventing the release of NF-κB. In addition, Se NPs also inhibit the expression COX-2 (Zhu et al. 2017). Se NPs incorporate into selenoproteins and inhibit PG-E2, ultimately inhibit COX-2.

Safety profile of metallic nanoparticle

Metallic nanoparticles (MNPs) are under considerable examination because of their growing use in a variety of sectors, including biomedicine, electronics, and environmental cleanup. While Metallic NPs show great promise for new uses, worries about their possible toxicity and environmental impact need a careful investigation. The safety of Metallic NPs is influenced by their physicochemical features, such as size, shape, surface charge, composition, and surface coating, as well as the route and length of exposure. Depending on how they interact with biological systems, Metallic NPs can have undesirable consequences such as cytotoxicity, genotoxicity, immunotoxicity, and oxidative stress (Agarwal and Shanmugam 2019). Furthermore, the biodistribution of Metallic NPs after exposure is critical for determining their biocompatibility and potential systemic consequences. Despite substantial study attempts to determine MNP safety, understanding their long-term toxicity and environmental fate remains a difficulty (Khan et al. 2019). As a result, ongoing research, extensive risk assessment, and regulatory monitoring are required to ensure MNPs are used safely and responsibly in a variety of applications. Developing standardised techniques for assessing the safety of metallic nanoparticles requires a multidisciplinary approach that combines nanotechnology, toxicology, pharmacology, and medicine. To begin, physicochemical characterisation of metallic nanoparticles is required, which includes factors such as size, shape, surface charge, composition, and stability. In vitro experiments using appropriate cell lines can assess cytotoxicity, genotoxicity, and immunotoxicity, providing preliminary data on nanoparticle biocompatibility and safety. Following animal studies are essential for determining acute and chronic toxicity, biodistribution, pharmacokinetics, and potential long-term consequences (Agarwal and Shanmugam 2019; Liu et al. 2021).Initially, clinical trials are required to assess the safety and efficacy of metallic nanoparticles in humans, taking into account dose regimens, route of administration, and long-term patient monitoring.

In terms of personalised therapy choices for rheumatoid arthritis (RA), the inflammatory variability needs individualised methods to meet individual differences in disease severity, progression, and medication response. Metallic nanoparticles offer intriguing options for personalised treatment in RA due to their versatility in drug delivery, targeted therapy, and inflammatory microenvironment modulation. MNPs can be functionalized with specific ligands or medications to target molecular pathways involved in RA pathogenesis, such as TNF-α or IL-6. This allows for personalised treatment options based on an individual's inflammatory profile (Unterberger et al. 2021). Furthermore, advances in biomarker identification and diagnostic technology enable the segmentation of RA patients into discrete subgroups based on their immunological and genetic profiles, allowing for targeted nanoparticle-based therapy suited to each patient's unique needs (Shafiey et al. 2018; Xu et al. 2020). The development of standardised techniques for assessing the safety of metallic nanoparticles is critical for their clinical application in RA therapy. Furthermore, the unique features of metallic nanoparticles provide interesting prospects for personalised therapy options based on an individual's specific inflammatory profile, thus advancing the paradigm of precision medicine in RA management.

Discussion and conclusion

The current work provides a comprehensive overview of the anti-inflammatory and anti-arthritis processes employed by different metallic and metallic oxide nanoparticles such as silver, gold, zinc oxide, iron oxides, selenium and titanium dioxide. The formation of a protein corona around nanoparticles increases their absorption by phagocyte cells. Many interactions between nanoparticles and cells, as well as the processes by which nanoparticles enter cells, have been addressed. Several general mechanisms underlying anti-inflammatory activity include the inhibition of pro-inflammatory cytokines, the scavenging of ROS, and the inhibition of the NF-B and COX-2 pathways. Since cytokines increase the immune response, blocking pro-inflammatory cytokines is one of the most significant methods. Nearly all metallic and metallic oxide nanoparticles use this strategy. The anti-inflammatory mechanisms of various nanoparticles can be used in medication design and targeting and they can also provide a likely answer for the treatment of rheumatoid arthritis with minimum side effects serving for precise therapy.

Author contribution

Shradha Devi Dwivedi: Methodology, software, writing—original draft, Anita Bhoi.: data curation, writing—original draft preparation. Madhulika Pradhan: validation., writing—reviewing and editing, formal analysis. Keshav Kant Sahu: conceptualization, visualization, writing—reviewing and editing, Deependra Singh: supervision, validation., writing—reviewing and editing, visualization. Manju Rawat Singh: conceptualization, resources, supervision, visualization, investigation, writing—reviewing and editing, funding acquisition.

Funding

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Data availability

No data were used for the research described in the article.

Declarations

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Authors have no conflict of interest.

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Research involving human participants and/or animals

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