Arthritis Therapy Research Articles

Targeted Therapy of Antibody-Induced Autoimmune Arthritis Using Peptide-Guided Nanoparticles

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and it affects over 18 million people worldwide. Despite the availability of a variety of potent drugs for RA, over 30–40 percent of patients fail to achieve adequate remission, and many patients suffer from systemic adverse effects. Thus, there is an urgent need for a joint-targeted drug delivery system. Nanotechnology-based drug delivery methods offer a promising resource that is largely untapped for RA. Using the T cell-driven rat adjuvant-induced arthritis (AA) model of human RA, we developed a peptide-targeted liposomal drug delivery system for arthritis therapy. It was based on a novel joint-homing peptide ART-2 to guide liposomes entrapping dexamethasone (Dex) to arthritic joints of rats, and this approach was more effective in suppressing arthritis than the unpackaged (free) drug. To de-risk the translation of our innovative drug delivery technology to RA patients, we undertook the validation of ART-2-liposomal delivery in a genetically and mechanistically distinct arthritis model in mice, the collagen antibody-induced arthritis (CAIA) model. Using live imaging for tissue distribution of liposomes in vivo, immunohistochemistry of paws for cellular binding of ART-2, and liposomal Dex delivery, our results fully validated the key findings of the rat model, namely, preferential homing of peptide-functionalized liposomes to arthritic joints compared to healthy joints, and higher efficacy of liposomal Dex than free Dex. These results offer a proof-of-concept for the benefits of targeted drug delivery to the joints and its potential translation to RA patients.

An Estimation of Baricitinib by AQbD-driven UV Spectrophotometry Development and Validation Process

Background: Baricitinib (BCTB) is a novel Janus Kinase (JAK) 1 and 2 inhibitor used in the therapy of rheumatoid arthritis, approved by the “Food and Drug Administration” in 2018. It has significant dose-dependent effectiveness and severe side effects. Thus, it is crucial to figure out its concentration in developed dosage forms. The literature search revealed that there has only been one UV spectroscopy technique documented up to this point. Methanol was chosen as the detection medium in this approach, which is not comparable with plasma or serum. As a result, the preliminary research suggested developing a UV spectroscopic approach that can estimate BCTB concentration and compare it to its concentration in the plasma or serum. Thus, in the proposed method, 7.4 pH phosphate buffer was selected as a mobile phase. Aim: Using the Analytical Quality by Design (AQbD) methodology, a simple, robust spectrophotometric method for the detection of BCTB in API form and Niosomes drug delivery system is designed and assessed. Methods: In the AQbD approach, a face-centered CCD design of Design Expert 13 software was used to evaluate two critical method variables: scanning speed and sampling interval. The design space suitability was confirmed by standard error and overlay plots. The 2-D contour and 3-D response surface plots were used to forecast the relationship between the response variable and predictor variables. Results: Baricitinib displays an absorption maximum at 249.40 nm in saline phosphate buffer pH 7.4. The distinguished linearity of the method was obtained over a concentration of 5–30 µg/ml with a correlation coefficient (R2 ) value of 0.998. BCTB % assay was found to be near 99 %. Intraday and Interday precision were found to have % RSDs of 0.067–0.488 and 0.146–0.942, respectively. Conclusion: The established spectrophotometric technique was observed to be precise as per ICH revised guidelines ICH Q2 (R1) and Q14 for analytical method validation. Our findings are instructional for the future design and development of safe and reliable therapeutic dosage forms of BCTB for rheumatoid arthritis.

PEGylated lipid polymeric nanoparticles for management of rheumatoid arthritis

PEGylation, an extensively used surface modification method for nanoparticles (NPs), continues to hold promise for optimizing therapy for various medical conditions by achieving efficient and selective delivery of multiple therapeutics and nanocarriers. Rheumatoid arthritis is a chronic autoimmune and inflammatory disease treated mainly by disease-modifying antirheumatic drugs (DMARDs) (e.g., leflunomide); however, these drugs suffer from systemic exposure and adverse effects. Leflunomide (LEF) was loaded into PEGylated (PEG)-lecithin chitosan nanoparticles (LCNPs) to enhance its therapeutic efficacy and safety profile. LEF-PEG-LCNPs showed a particle size of 115.31 ±3.24 nm, a zeta potential of 31.3±1.8 mV, an entrapment efficiency of 89.63 ±2.25 %, and an improved release profile than non-pegylated LCNPs and LEF-pure. Fourier transform-infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and transmission electron microscopy (TEM) were also performed. The effects of orally administrated LEF-pure, LEF-marketed, LEF-LCNPs and LEF-PEG-LCNPs against Complete Freund’s Adjuvant (CFA)-induced rheumatoid arthritis (RA) in rats were investigated. LEF-PEG-LCNPs showed more significant inhibition of paw edema (72.74%), rheumatoid factor RF (40.76%), TNF-α (55.6%), IL-6 (47.42%), ALT (80.59%), and AST (39.83%) as compared to positive control. Furthermore, histopathological studies showed a nearly normal appearance of bone trabecular tissue, liver, kidney, lung, and heart. This highlights LEF-PEG-LCNPs as an exceptional anti-rheumatoid arthritis therapy compared to pure and marketed formulations.

Au/Ag@ZnS yolk-shell photocatalysts enhanced with noble metals and hyaluronic acid for efficient hydrogen production in rheumatoid arthritis therapy

Rheumatoid arthritis, characterized by the abnormal proliferation of synovial cells and extensive macrophage infiltration, is a chronic inflammatory disease. Molecular hydrogen, known for its antioxidant properties, has shown promise in eliminating reactive oxygen species. However, the low solubility and bioavailability of hydrogen limit the effectiveness of this therapy. To overcome these issues, we developed a novel yolk-shell heterostructure, H-AAZS (Au/Ag@ZnS modified hyaluronic acid), utilizing a hydrothermal cation exchange process. Through ion doping, semiconductor hybridization, and Schottky barriers in H-AAZS, photocatalysis for hydrogen generation has been successfully implemented using 660 nm laser irradiation. Additionally, the H-AAZS demonstrate the capacity for mild photothermal therapy, inducing apoptosis in synovial cells with Au's hot electrons with 660 nm laser irradiation. This strategy not only improves the abnormal proliferation of synovial cells but also avoids the exacerbation of inflammation caused by thermal stimulation. Both in vitro and in vivo experiments validate the synergistic effects of hydrogen production mediated anti-inflammatory responses, macrophage polarization and photothermal therapy. Therefore, this work represents a significant advancement as it ingeniously harnesses photocatalysis to modulate the synovial microenvironment while mitigating the side effects associated with photothermal therapy. This nanocrystal provides new and valuable insights into the potential treatment of Rheumatoid arthritis.

Infiltrations of plasma cells in synovium predict inadequate response to Adalimumab in Rheumatoid Arthritis patients

ObjectiveRheumatoid arthritis (RA) is a clinically heterogeneous and complex autoimmune disease, making the prediction of therapeutic responses a significant challenge. This study aims to assess the role of clinical and synovial biomarkers in predicting poor response to adalimumab treatment in RA patients.MethodsThis single-center prospective study included 56 RA patients who had an inadequate response to methotrexate (MTX). At baseline, comprehensive assessments including complete blood count, liver and kidney function tests, blood glucose levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), as well as counts of swollen and tender joints, Health Assessment Questionnaire (HAQ) score, pain visual analogue scale (VAS) scores, and DAS28-CRP scores were conducted. Synovial biopsies were performed, followed by an efficacy evaluation at 12 weeks of adalimumab treatment. Patients not meeting the ACR20 criteria were classified into the non-responder group, with the remainder categorized as the responder group.ResultsOut of the participants, 24 (42.9%) failed to achieve ACR20 with adalimumab treatment. Non-responders exhibited higher infiltration of plasma cells in the synovium. Multivariate logistic regression analysis identified the presence of plasma cells as an independent risk factor for inadequate response to adalimumab.ConclusionInadequate responses to adalimumab in RA patients were associated with increased plasma cell infiltrations in the synovium. These findings suggest a promising target for tailored therapies in rheumatoid arthritis.

The recent progress of γδ T cells and its targeted therapies in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune condition that mostly impacts the joints. During the advanced phases of the disorder, it may be accompanied by other problems. While the precise cause of RA is uncertain, various research has been conducted to gain a better understanding of the immunological processes involved in the development of RA. T cells are acknowledged as significant contributors to the progression of RA because of their roles in cytokine secretion, antigen presentation, and facilitating B cells in the manufacture of antibodies. γδ T cells are a small subset of T cells that have significant functions in the context of infection and diseases linked with tumors. γδ T cells have been the subject of investigation in autoimmune disorders in recent years. This review focused on the involvement of γδ T lymphocytes in the development of RA. In this article, we provide an analysis of the immunological capabilities of γδ T cells, intending to comprehend their significance in RA, which could be pivotal in the creation of innovative clinical treatments.

Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Deciphering farnesol's anti-arthritic and immunomodulatory potential by targeting multiple pathways: a combination of network pharmacology guided exploration and experimental verification.

Farnesol (FAR), a sesquiterpene alcohol, has documented FAR's anti-inflammatory and antioxidant activities. Current study was undertaken to assess the efficacy and mechanism of FAR in arthritis by employing network pharmacology and experimental models. Two experimental models comprising formaldehyde- and complete Freund's adjuvant (CFA)-induced arthritis evaluated the efficacy of FAR in treating arthritis. Various parameters were assessed. Then, a network pharmacology approach was applied to gain further insight into the potential mechanism and signaling pathways. FAR significantly reduced paw volume and the arthritic score and improved the hematological and biochemical changes. Radiographic and histological examination showed the anti-arthritic efficacy of FAR, which was associated with down-regulation of pro-inflammatory mediators and upregulation of anti-inflammatory mediators. Network pharmacology analysis revealed that FAR may exert its anti-arthritic effects by targeting specific genes associated with arthritis. Pathway analysis revealed the involvement of three key signaling pathways (IL-17 signaling, TNF signaling, and toll-like receptor signaling) in the development and progression of arthritis. The results pointed out the protective attributes of farnesol against formaldehyde and CFA-induced arthritis via modulation of multiple targets. This study provides a valuable reference for the development of a new treatment or complementary therapy for arthritis.

B-221 Combined RT-PCR and Whole Exome Sequencing Pharmacogenetic Testing in Polypharmacy Patient: A Case Report

Abstract Background Pharmacogenetics has become one of the main branches of Precision Medicine owing to its usefulness for patients’s optimal therapeutic management. Notwithstanding, pharmacogenetic testing results must be taken carefully, specially in multimorbidity patients with a variety of drugs prescribed. The aim of the present work is to introduce a combined RT-PCR and Whole Exome Sequencing Approach for pharmacogenetic testing in a patient with multiple drug-related adverse events. Case Background A 67 years old female was derived to our Clinical Chemistry Unit for pharmacogenetic testing due to multiple drug-related adverse events: nifedipine-voriconazole interaction, voriconazole-related neurological toxicity and moxifloxacin-related dizziness. Aditionally, she had been receiving morphine, corticoid for her reumatoid arthritis and antituberculous therapy (r isoniazid / pyrazinamide / rifampin and ethambutol). Methods Patient’s DNA was extracted from a blood sample and undergone by pharmacogenetic testing in two parallel ways: -A first genotyping assay was carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™), according to manufacturer’s instructions. -Simultaneusly, in order to cover possible copy number variants and SNPs not covered by our RT-PCR array, a whole exome sequencing run was performed on IlluminaTM NextSeq 1000. Sample library was prepared applying a custom GRCh38 pipeline. Results Relevant variants related to patient’s therapy found by RT-PCR are shown in table 1. SNPs genotyped by RT-PCR were confirmed by NGS. Moreover, whole exome sequencing revealed a deletion in exon 5 of SLCO1B1 gene, which corresponds to SLCO1B1*49 (loss of function); and some variants in NAT2 that may cause toxicity in antituberculous treatment (diplotype NAT2*6C/*7C). Conclusions In those challenging cases that involve multimorbidity and polypharmacy patients, pharmacogenetic testing must be approached taking into account variants that are not covered by the analytical method routinely used and the possibility of complement it with alternative proccedures.

Proximod as a potential therapy for rheumatoid arthritis

Proximod as a potential therapy for rheumatoid arthritis

Disease response in rheumatoid arthritis across four biologic therapies associates with improvement in paraoxonase-1 activity and oxylipins

ObjectiveParaoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different...

Repetitive intra-articular therapy in fungal arthritis: Adjunct to systemic therapy in a patient with pediatric acute lymphoblastic leukemia

Repetitive intra-articular therapy in fungal arthritis: Adjunct to systemic therapy in a patient with pediatric acute lymphoblastic leukemia

Update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological and synthetic targeted therapies in rheumatoid arthritis

ObjectiveTo update the consensus document of the Spanish Society of Rheumatology (SER) regarding the use of targeted biological and synthetic therapies in rheumatoid arthritis (RA) with the aim of assisting clinicians in their therapeutic decisions. MethodsA panel of 13 experts was assembled through an open call by SER. We employed a mixed adaptation-elaboration-update methodology starting from the 2015 Consensus Document of the Spanish Society of Rheumatology on the use of biological therapies in RA. Starting with systematic reviews (SR) of recommendations from EULAR 2019, American College of Rheumatology 2021, and GUIPCAR 2017, we updated the search strategies for the PICO questions of GUIPCAR. An additional SR was conducted on demyelinating disease in relation to targeted biological and synthetic therapies. Following the analysis of evidence by different panelists, consensus on the wording and level of agreement for each recommendation was reached in a face-to-face meeting. ResultsThe panel established 5 general principles and 15 recommendations on the management of RA. These encompassed crucial aspects such as the importance of early treatment, therapeutic goals in RA, monitoring frequency, the use of glucocorticoids, the application of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs. Additionally, recommendations on dose reduction of these drugs in stable patients were included. This update also features recommendations on the use of bDMARDs and Janus Kinase inhibitors in some specific clinical situations, such as patients with lung disease, a history of cancer, heart failure, or demyelinating disease. ConclusionsThis update provides recommendations on key aspects in the management of RA using targeted biological and synthetic therapies.

Harnessing marine natural products to inhibit PAD4 triple mutant: A structure-based virtual screening approach for rheumatoid arthritis therapy

Peptidylarginine deiminase type4 (PAD4) is a pivotal pro-inflammatory protein within the human immune system, intricately involved in both inflammatory processes and immune responses. Its role extends to the generation of diverse immune cell types, including T cells, B cells, natural killer cells, and dendritic cells. PAD4 has recently garnered attention due to its association with a spectrum of inflammatory and autoimmune disorders, notably rheumatoid arthritis (RA). Mutations in the PAD4 gene, leading to the conversion of arginine to citrulline, have emerged as significant factors in the pathogenesis of RA and related conditions. As a calcium-dependent enzyme, PAD4 is central to the citrullination process, a crucial post-translational modification implicated in disease pathophysiology. Its critical role in autoimmune disorders and inflammation makes PAD4 a prime candidate for therapeutic intervention in RA. Inhibiting PAD4 presents a promising avenue for mitigating inflammatory responses and curtailing joint degradation and impairment. To explore its therapeutic potential, a structure-based virtual screening (SBVS) approach was employed, harnessing an array of marine natural products (MNPs) sourced from databases such as CMNPD, MNPD, and Seaweed. Notably, MNPD10752, CMNPD12680, and CMNPD2751 emerged as potential hit molecules, exhibiting adherence to essential pharmacokinetic properties and favorable toxicity profiles. Quantum mechanics studies using density functional theory (DFT) calculations revealed the inhibitory potential of these identified natural products. Further structural elucidation through molecular dynamics simulations (MDS) and principal component-based free energy landscape (FEL) analysis shed light on the stability of MNP-bound PAD4 complexes. In conclusion, this computational study serves as a stepping stone for further experimental evaluation, aiming to explore the potential of MNPs in addressing PAD4-related human pathologies.

Biological therapy for psoriatic arthritis: current state and future perspectives

Biological therapy for psoriatic arthritis: current state and future perspectives

Clinical outcomes of tocilizumab therapy in polyarticular and systemic juvenile idiopathic arthritis: a single-center analysis (2018-2022)

AbstractThis single-center retrospective study aimed to evaluate the safety and efficacy of Tocilizumab (TOC) in children with polyarticular (pJIA) and systemic juvenile idiopathic arthritis (sJIA) who exhibited inadequate responses to disease-modifying antirheumatic drugs (DMARDs) and biological modifiers (bDMARDs). Conducted at the Department of Pediatric Rheumatology, National Institute of Geriatrics, Rheumatology, and Rehabilitation in Warsaw, Poland, between 2018 and 2022, the study enrolled 29 patients diagnosed with JIA based on International League of Associations for Rheumatology (ILAR) criteria. The cohort comprised 13 sJIA and 16 pJIA patients, aged 2-18 years, receiving TOC treatment for 24 months. Safety and efficacy assessments included analysis of medical documentation, laboratory tests (CRP, ESR, WBC), and Juvenile Disease Activity Score (JADAS) 71 at baseline, 3, 6, 12, and 24 months post-treatment initiation. Significant reductions in CRP and ESR levels were observed within three months, with sustained improvement in JADAS71 scores over the 24-month treatment period. A substantial majority, 73.07% of patients, achieved inactive disease status or low disease activity, highlighting T0C’s effectiveness. Adverse effects were manageable, predominantly involving mild to moderate infections, with no serious adverse events or instances of macrophage activation syndrome (MAS). The study also noted a steroid-sparing effect of TOC, with a reduction in glucocorticoid usage among the cohort. Tocilizumab demonstrates substantial efficacy in reducing disease activity and improving clinical outcomes in patients with pJIA and sJIA, coupled with a favorable safety profile. These findings reinforce the role of TOC as a critical component of the therapeutic arsenal for JIA, offering hope for improved quality of life and disease management in this patient population.

Tofacitinib treatment for plaque psoriasis and psoriatic arthritis: A meta-analysis of randomised controlled trials.

Objectives Tofacitinib is used as an oral Janus-associated kinase (JAK) inhibitor acting on JAK1 and JAK3, in treating psoriatic disease. However, there is still no consensus on the optimal dosage and duration of tofacitinib. In this study, we aimed to evaluate the effects of tofacitinib in treating psoriatic disease. Methods and Materials A literature search was done utilising Cochrane library, Medline, EMBASE, Wiley Online library, Web of Science and BIOSIS Previews through December 18, 2022. We performed a meta-analysis of published original studies to assess the impact of tofacitinib in plaque psoriasis or psoriatic arthritis therapy based on seven randomised controlled trials (RCTs) involving 2,672 patients (receiving tofacitinib) and 853 controls (receiving placebo). Results Compared with placebo, the treatment of 5 mg twice-daily (BID) tofacitinib for 12 weeks is sufficient to significantly alleviate the main clinical manifestations of psoriasis [≥75% decrease in Psoriasis Area and Severity Index score (PASI 75): Risk ratio (RR)=4.38 (95% Confidence interval (CI) 2.51 to 7.64); ≥90% decrease in PASI score (PASI 90): RR=21.68 (95% CI 4.20 to 111.85); Physician's Global Assessment of 'clear' or 'almost clear' (PGA 0/1): RR=3.93 (95%CI 3.03 to 5.09)]. Interestingly, there was no significant difference in improvement in PGA 0/1 with 5 mg BID tofacitinib given for 16 weeks when compared with 5 mg BID tofacitinib for 12 weeks [RR=1.11 (95%CI 0.98 to 1.25)]. Additionally, the 5 mg BID tofacitinib for 16 weeks treatment schedule significantly increased the incidence of upper respiratory tract infection (URTI) [RR=1.89 (95%CI 1.06 to 3.38)] as compared to 5 mg BID tofacitinib for 12 weeks treatment schedule [RR=1.15 (95%CI 0.60 to 2.20)]. Conclusion The 5 mg BID tofacitinib for 12 weeks treatment significantly improved psoriasis without causing too many specific adverse events. This indicated that tofacitinib is an effective treatment plan for psoriatic disease by reasonably controlling dosage and dosing time.

Decision Aid-Led Tapering of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Qualitative Study.

To explore the experiences and perspectives of patients and rheumatologists on decision aid (DA)-led tapering of advanced therapy in rheumatoid arthritis (RA). Semistructured interviews were completed with patients and rheumatologists, embedded within a pilot study of DA-led tapering (ie, dose reduction) of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) in RA. All patients were in sustained (≥ 6 mos) remission and had chosen to reduce their therapy after a DA-led shared decision with their rheumatologist. The rheumatologists included those participating in the pilot (n = 4), and those who were not (n = 8). Reflexive thematic analysis of audiotaped and transcribed interviews identified themes in the group experiences. Patients (n = 10, 6 female) unanimously found the DA easy to understand and felt confident in shared decision making about treatment tapering and managing flares. Rheumatologists' (n = 12, 5 female) perspectives on tapering bDMARDs and tsDMARDs varied widely, from very supportive to completely opposed, and influenced their views on the DA. Rheumatologists expressed concerns about patient comprehension, destabilizing a stable situation, risks of flare, and extending appointment times. Despite their initial reservations about sending the DA to all eligible patients ahead of appointments, 3 of 4 participating rheumatologists adopted this approach during the pilot, which had the benefit of facilitating patient-led conversations. A DA-led strategy for tapering advanced therapy in RA was acceptable to patients and feasible in practice. Sending patients a DA ahead of their appointment facilitated patient-led conversations about tapering.

Fabrication of a novel macrophage-targeted biomimetic delivery composite hydrogel with multiple-sensitive properties for tri-modal combination therapy of rheumatoid arthritis

In this study, a porous polydopamine (PDA) nanoparticle-decorated β-glucan microcapsules (GMs) nanoplatform (PDA/GMs) were developed with macrophage-targeted biomimetic features and a carriers-within-carriers structure. Indocyanine green (ICG) and catalase (CAT) were subsequently co-encapsulated within the PDA/GMs to create a multifunctional nanotherapeutic agent, termed CIPGs. Furthermore, CIPGs and sinomenine (SIN) were co-loaded within a thermo-sensitive hydrogel to design an injectable delivery system, termed CIPG/SH, with potential for multi-modal therapy of rheumatoid arthritis (RA). Photothermal studies indicated that the CIPGs hold excellent photothermal conversion ability and thermal stability, as they combined the photothermal performance of both PDA and ICG. Meanwhile, the CIPGs displayed favorable oxygen self-supplying and photodynamic performance. The CIPGs showed near-infrared (NIR)-induced phototoxicity, effectively inhibiting macrophage proliferation and displaying remarkable antibacterial activity. In vitro drug release from the prepared CIPG/SH showed a controlled release pattern. Animal experiments conducted on an RA mice model confirmed that the formulated CIPG/SH exhibited significant therapeutic effects. By integrating the biological advantages, photothermal/photodynamic performance of the CIPGs, and controlled drug release performance of the thermo-sensitive hydrogels in a single delivery system, the prepared injectable CIPG/SH represents a novel versatile delivery system with great potential for multi-modal combination targeting therapy in RA.

Prolonged, staged, and self-regulated methotrexate release coupled with ROS scavenging in an injectable hydrogel for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) remains a formidable healthcare challenge due to its chronic nature and potential for irreversible joint damage. Methotrexate (MTX) is a cornerstone treatment for RA but carries significant risks of adverse effects with repeated administration, necessitating the exploration of alternative delivery methods. Injectable hydrogels loaded with MTX for intra-articular injection present a promising solution, allowing sustained drug release directly into affected joints. However, current hydrogel systems often lack extended therapeutic periods and the ability to self-regulate drug release according to disease state. Furthermore, RA is associated with excessive production of reactive oxygen species (ROS), which exacerbates inflammation and joint damage. Herein, we developed an advanced injectable hydrogel (MPDANPs/MTX HA-PEG gel) based on “bio-orthogonal chemistry”, combining hyaluronic acid and polyethylene glycol (PEG) matrices co-loaded with mesoporous polydopamine nanoparticles (MPDANPs) and MTX. MPDANPs/MTX HA-PEG gel achieved prolonged, staged, and self-regulated MTX release, coupled with ROS scavenging capabilities for enhanced therapeutic efficacy. Due to its optimized MTX release behavior and significant ROS scavenging function, MPDANPs/MTX HA-PEG gel exhibited potent anti-inflammatory effects in collagen-induced arthritis (CIA) rats following a single intra-articular injection. Our findings highlight the potential of MPDANPs/MTX HA-PEG gel as a highly effective treatment strategy for RA, offering a promising avenue for improving patient outcomes.