DOI: 10.1097/cm9.0000000000004305 ISSN: 0366-6999

Extracellular matrix targeting peptide functionalized plant-derived lipid nanoparticles for gene therapy in osteoarthritis

Zoya Iqbal, Maryum Shabbir, Faiz Rasul, Jiang Xia, Hui Zeng, Yujie Liang, Li Duan
Show PDF Cite

Abstract

Background:

The pathogenesis of osteoarthritis (OA) involves the degradation of the extracellular matrix (ECM) of cartilage, which is mainly mediated by matrix metalloproteinases (MMPs). Small interfering RNA (siRNA)-based gene therapy has shown promise in treating various diseases, including OA, but its effectiveness is hindered by poor stability and low uptake efficiency. Additionally, the avascular nature of cartilage poses a challenge for drug delivery. This study aims to develop a novel plant-derived nanoparticle system for targeted, efficient delivery of siRNA to intra-articular chondrocytes, thereby alleviating OA progression.

Methods:

We designed lipid nanoparticles (LNPs) based on lipids extracted from grapefruit extracellular vesicles (GEVs), which were functionalized with an ECM-binding peptide derived from placenta growth factor-2 (PIGF-2). siRNA targeting MMP13 was loaded, and the therapeutic efficacy and safety were evaluated in both the cellular and rat OA models.

Results:

These PIGF2-LNPs delivering siRNA MMP13 , termed PIGF2-siRNA MMP13 -LNPs, were uniform in size (196 nm) and stable with a zeta potential of –9.96 ± 0.49 mV. The system delivered siRNA targeting MMP13 to chondrocytes. The PIGF2-modified LNPs exhibited high biocompatibility and low toxicity, and the PIGF2 peptide conferred specific chondrocyte-targeting ability, significantly enhancing cellular uptake. The system enhanced the siRNA-mediated gene silencing of MMP13 , a key enzyme involved in cartilage degradation. The PIGF2-siRNA MMP13 -LNPs effectively suppressed MMP13 protein expression ( P <0.001) and increased collagen II protein expression ( P <0.05) and lowered the Osteoarthritis Research Society International (OARSI) score ( P <0.001) in rat chondrocytes.

Conclusions:

This study developed biocompatible grapefruit-derived LNPs for targeted intra-articular siRNA delivery. The peptide-functionalized LNPs effectively silenced MMP-13 in chondrocytes. The system attenuated the hydrolytic degradation of ECM proteins in cartilage and mitigated OA progression in a rat model, with minimal toxicity, suggesting a promising plant-based, cell-free, targeted therapy for OA.

More from our Archive