Top-Down Fabricated microPlates for Prolonged, Intra-articular Matrix Metalloproteinase 13 siRNA Nanocarrier Delivery to Reduce Post-traumatic Osteoarthritis

Abstract

Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA) based microPlates (μPLs) to formulate siNP-μPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-μPLs against MMP13 (siMMP13-μPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65−75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-μPL therapy for PTOA.

Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage

“…DEX-μPLs effectively protected articular cartilage and joint structure in the PTOA model. Not only that, μPLs could also carry short interfering RNA (siRNA) loaded nanoparticles (siNPs) of MMP13 ( Figure 4 ) (Bedingfield et al., 2021 ). The findings showed that it could remain in the PTOA model for more than 10 days and maintained down-regulation of the MMP13 gene and reduced levels of MMP13 protein in the joints throughout the 28-day study.…”

“…Duvall et al. attached a Col2 monoclonal antibody (mAbCII) to the surface of polymeric siRNA nanoparticle complexes (siNPs) (Bedingfield et al., 2021 ). They build a nanoparticle that could target and penetrate cartilage with approximately 100 nm and approximately zeta potential.…”

Management of osteoarthritis: From drug molecules to nano/micromedicines

“…It was hypothesized that the unique flat shape and mechanical property of the particles complementarily aided in the process of lubrication (Figure 5 ; Di Francesco et al, 2021 ). Additionally, the same particles were used for delivering matrix metalloproteinase 13 (MMP‐13) interfering RNA loaded nanoparticles (siMMP13‐NPs) in the same animal model (Bedingfield, Colazo, Di Francesco, et al, 2021 ). In particular, the authors demonstrated that the combination of siRNA NPs with microparticles (siMMP13‐NPs loaded μPLs) significantly increased the residence time in the joint compared with the free NPs.…”

“…In particular, the authors demonstrated that the combination of siRNA NPs with microparticles (siMMP13‐NPs loaded μPLs) significantly increased the residence time in the joint compared with the free NPs. Also, the gene silencing effect of siMMP13‐NPs loaded μPLs in‐vivo was maintained for 28 days after a single IA injection, thereby reducing all the problems associated with MMP‐13 activities in the progression of the disease itself (Bedingfield, Colazo, Di Francesco, et al, 2021 ). Different polymers including chitosan or synthetic materials like PEG, poly(caprolactone) (PCL), and poly(propylene sulfide) (PPS) have been utilized to develop similar slow releasing platforms.…”

Recent Advances in Nano-Therapeutic Strategies for Osteoarthritis

“…The researchers also designed small interfering RNA (siRNA)-loaded nanoparticles (siNPs) that were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA)-based microplates to maintain siNPs in the joint significantly longer than delivery of free siNPs. They enabled long-lasting therapy for post-traumatic OA by silencing MMP13 ( Bedingfield et al, 2021a ). Li et al constructed a responsive MS@G5-AHP/miR-140 “nano-micron” combined microfluidic gene-hydrogel microspheres (MSs) to alleviate the degradation of articular cartilage as a novel strategy for regional gene therapy ( Li et al, 2022 ).…”