Intra-articular nanoparticles based therapies for osteoarthritis and rheumatoid arthritis management

Abstract

Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic and progressive inflammatory joint diseases that affect a large population worldwide. Intra-articular administration of various therapeutics is applied to alleviate pain, prevent further progression, and promote cartilage regeneration and bone remodeling in both OA and RA. However, the effectiveness of intra-articular injection with traditional drugs is uncertain and controversial due to issues such as rapid drug clearance and the barrier afforded by the dense structure of cartilage. Nanoparticles can improve the efficacy of intra-articular injection by facilitating controlled drug release, prolonged retention time, and enhanced penetration into joint tissue. This review systematically summarizes nanoparticle-based therapies for OA and RA management. Firstly, we explore the interaction between nanoparticles and joints, including articular fluids and cells. This is followed by a comprehensive analysis of current nanoparticles designed for OA/RA, divided into two categories based on therapeutic mechanisms: direct therapeutic nanoparticles and nanoparticles-based drug delivery systems. We highlight nanoparticle design for tissue/cell targeting and controlled drug release before discussing challenges of nanoparticle-based therapies for efficient OA and RA treatment and their future clinical translation. We anticipate that rationally designed local injection of nanoparticles will be more effective, convenient, and safer than the current therapeutic approach.

Keywords: Controlled release; Drug delivery; Intra-articular; Nanoparticles; Osteoarthritis; Rheumatoid arthritis.

Graphical abstract

Fig. 1

Anatomy of joint under healthy, OA and RA condition.

Fig. 2

Intra-articular injection of direct therapeutic and drug delivery nanoparticles for OA and RA. Possible interactions of nanoparticles with components in joints are illustrated. A, intra-articular injection of nanoparticles for OA and RA; B, nanoparticles interacting with extracellular matrix (ECM); C, nanoparticles interacting with synovial fluid; D, nanoparticles interacting with immune cells, chondrocytes or synoviocytes. Nanoparticles or their degradation products exit the joint via drainage through the lymphatics and capillaries underlying the synovium. NP, nanoparticle; MPS, mononuclear phagocyte system; HA, hyaluronic acid.

Fig. 3

Intra-articular nanoparticles for OA and RA management. Based on their working mechanisms and functions, direct therapeutic nanoparticles and drug delivery systems are divided.

Fig. 4

Nanoparticles with neutrophil membrane coatings minimize arthritic joint degeneration and synovial inflammation in RA. A, Neutrophil-nanoparticles were shown schematically; B, transmission electron microscope (TEM) images of Neutrophil-nanoparticles (uranyl acetate were used to stain samples, Scale bar, 100 ​nm); C, after being incubated with neutrophil-nanoparticles or red blood cell-nanoparticles, fluorescent pictures of chondrocytes and human umbilical vein endothelial cells were presented. Blue and red stand for nuclei and nanoparticles, respectively. Cells were stimulated with TNF-α previously. Scale bar, 50 ​μm; D-E, Neutrophil-nanoparticles affected chondrocyte activation (D), apoptosis (D), and release of MMP-3 (E); F, H&E and safranin-O staining images of mice's knee sections treated with neutrophil-nanoparticles, phosphate buffered saline (PBS), anti-IL-1β antibody, or anti- TNF-α antibody. Scale bars, 100 ​μm; G, Safranin-O stained knee slices were employed to calculate the amount of cartilage present. Scale bars, 100 ​μm. Reproduced from Ref. [97] with permission from Elsevier.

Fig. 5

Hyaluronan synthase 2 is being delivered via MSNs with a core-cone structure and surface-functionalized with polyethylenimine to improve native hyaluronan generation. A, Nanoparticles mediated Hyaluronan synthase 2 delivery to synoviocytes; B, MSNs with a core-cone structure and surface-functionalized with polyethylenimine examination by TEM (a), scanning electron microscope (SEM) (b), and electron tomography (ET) (c); C, Representative immunoblots and D, quantitative information on the levels of Hyaluronan synthase 2, CD44, and high mobility group box 1 protein expression in synoviocytes; E, MicroCT scans of the temporomandibular joint condyles with sagittal section views at 2 and 12 weeks following monoiodoacetate injection. Reproduced from Ref. [131] with permission from John Wiley and Sons.

Fig. 6

A collagen-binding peptide (WYRGRLC) was incorporated in lipid-polymer hybrid nanoparticles for targeting cartilage. A) Illustration of the hybrid nanoparticle, which has a PLGA-core and a PEG-conjugated lipid shell. The particles can penetrate the cartilage intensely with drug release for chondrocytes; B) The hydrodynamic diameter of the corresponding PLGA cores, lipid-polymer hybrid nanoparticles, and collagen-targeting lipid-polymer hybrid nanoparticles; C) The zeta potential (mV) of various nanoparticles; D) A typical TEM picture of collagen-targeting lipid-polymer hybrid nanoparticles stained with uranyl acetate (scale bar, 50 ​nm); E) Fluorescence images of femoral head slices treated with collagen-targeting lipid-polymer hybrid nanoparticles (bottom) or DiD-labeled lipid-polymer hybrid nanoparticles (top). The nanoparticles are shown in red, and the nuclei are shown in blue (scale bars: 20 ​μm); F) After intra-articular injection of fluorescently tagged nanoparticles at various timepoints, pictures of mice knee joints were captured. G) cartilage slice images, stained with Safranin-O, from healthy mice (Naive), OA mice treated with PBS, lipid-polymer hybrid nanoparticles (MK-8722), and collagen-targeting lipid-polymer hybrid nanoparticles (MK-8722), respectively. Scale bars, 100 ​μm; H) TNF-α, IL-1β, and nitric oxide synthase 2-related mRNA expression in the mice's knee cartilage after treatment with different agents. Reproduced from Ref. [144]with permission from John Wiley and Sons.

Fig. 7

HA nanoparticles were constructed to target the CD44 receptor and ameliorate OA. A) Scheme of the HA nanoparticles induced OA therapy; B) TEM images and size distribution of HA-nanoparticles. Scale bar, 100 ​nm; C) Sequential images of the femoral cartilages after normal mice were intra-articularly injected Cy5.5 and Cy5.5-labeled HA-nanoparticles. Scale bars, 100 ​μm; D-E) OA mouse cartilage injected intra-articularly once a week with PBS, HA-nanoparticles, or free high-molecular-weight HA 4 weeks post destabilization of the medial meniscus surgery. Relevant Safranin O, CD44 staining, Osteoarthritis Research Society International (OARSI) grade, and subchondral bone plate thickness were displayed. (F–I) IκB levels in IL-1β-treated (F,G) and Ad-Cd44-infected (H,I) chondrocytes with or without HA-nanoparticles. Reproduced from Ref. [80] with permission from Elsevier.

Fig. 8

Ameliorating post-traumatic OA with collagen type II antibodies decorated nanoparticles that deliver siRNA. A) Scheme of matrix-targeted nanoparticles which augment siRNA intracellular activity and retention in cartilage damaged locations; B) Formulation scheme for siRNA cargo packing and construction; C) ATDC5 cells activated with TNF were treated with the targeting nanoparticles to silence MMP-13 (siMMP-13 against 50 ​nM or 100 ​nM nontargeting siRNA sequences); D) Targeting nanoparticles' retention on both healthy and trypsin-damaged porcine cartilage explants was assessed by using intravital in vivo imaging system (IVIS) imaging of rhodamine-fluorescing polymers. E-H) Long-term MMP-13 knockdown lowered MMP-13 protein levels in cartilage, synovium and allieviated the progress of OA in mechanically stressed joints. Schematic of the Long-term OA mouse model E); MMP-13 expression at the end of week 6 (siMMP-13 versus nontargeting siRNA sequences F); immunohistochemical staining demonstrating decreased MMP-13 protein levels in cartilage when administered with the targeting nanoparticles G); Characteristic images of Safranin O stained cartilage of the femurs in healthy mice (top left) and OA mice treated with siMMP-13, nontargeting siRNA sequences or no treatment; FL, lateral femoral condyle H). Reproduced from Ref. [152] with permission from Elsevier.

Fig. 9

Modified ZIF-8 nanoparticles alleviated OA via modulating synovial macrophages' metabolic pathways. A) Synthesis of Modified ZIF-8 nanoparticles; B, C) Intracellular gases were regulated via administration of the nanoparticles, dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe assisting measurement of M1 macrophages' intracellular H2O2 level B), the O2 indicator [Ru (dpp)3]2 ​+ ​Cl2] assisting measurement of intracellular O2 level C); D) Western blot of HIF-1α; E) IVIS imaging of intra-articularly injected nanoparticles; F) H&E staining of the cartilage in knee joints of OA mice after nanoparticle therapy. Reproduced from Ref. [155] with permission from American Chemical Society.

Fig. 10

PH-responsive HA-MOF mediated OA treatment. A-C) TEM images of MOF(A), MOF@HA(B) and MOF@HA@protocatechuic acid(C); D) Immunofluorescent staining detected MMP-13 expression (scale bar: 100 ​μm); E) Safranin O/fast green staining of cartilage after treatment for 4 and 8 weeks (scale bar: 500 ​μm); F) Osteoarthritis Research Society International scores for articular cartilage histology after 4 and 8 weeks of treatment. Reproduced from Ref. [177] with permission from BioMed Central.