Nanomaterial-Based Drug Delivery Systems Targeting Functional Cells for Osteoarthritis Treatment: Mechanisms, Challenges and Future Prospects

Abstract

Osteoarthritis (OA) represents a chronic joint disease characterized by articular cartilage degeneration, synovial inflammation, and subchondral bone erosions. Functional cells in OA mainly include macrophages, synoviocytes, chondrocytes, and mesenchymal stem cells. These cells can secrete cytokines and non-coding RNAs and exosomes and interact with each other to coregulate the progression of OA. Some nanomaterial-based drug delivery systems (DDSs) surface ligands can alleviate OA by targeting receptors on the surface of functional cells. Meanwhile, other nanomaterial-based DDSs, whose surfaces are masked by the cell membranes or extracellular vesicles of these functional cells, treat OA by targeting and attacking the diseased site. When ligand-modified nanomaterials target specific functional cells to treat OA, the functional cells are attacked. Functional cells become attackers, similar to arrows, when their cell membranes or extracellular vesicles are modified into nanomaterials to deliver drugs for OA treatment. An increasing number of studies have been conducted on nanomaterial-based DDS-targeted functional cells for the treatment of OA, but none has summarized the corresponding research progress and mechanism of action. In this review, the related references on the treatment of osteoarthritis with nanomaterial-based DDSs targeting functional cells have been included, and how a variety of functional cells can be engineered into nanomaterial-based DDSs serving as targets or arrows to treat OA has been summarised for the first time, providing a new idea and method for the targeted treatment of OA.

Keywords: chondrocytes; macrophages; mesenchymal stem cells; nanomaterial-based drug delivery systems; osteoarthritis; synoviocytes.

Graphical abstract

Figure 1

Therapeutic targets for OA. Therapeutic targets for OA can be divided into three main categories. First, macrophages, synoviocytes, mesenchymal stem cells and chondrocytes can be targeted by CRISPR-based gene editing technology, exosome delivery technology and nanomaterial-based drug delivery technology. Secondly, inflammatory factors such as TNF-α, IL-1β and IL-6 and anti-inflammatory factors such as IL-10 and IL-4 can be targeted by inhibitor, blocking agents, monoclonal antibodies against and exogenous administration of factors. Thirdly, inhibitors or activators of enzymes and signalling pathways can target various enzymes and signalling pathways associated with the onset and development of OA.

Figure 2

Nanomaterial-based DDSs treat OA by targeting macrophages. Nanomedicines modified with different ligands target macrophages through the corresponding receptors on macrophages to release functional drugs. Different nanomedicines regulate macrophages through different mechanisms. Firstly, nanomedicines reduce circulating cell-free DNA by down-regulating the mTOR signaling pathway. Secondly, nanomedicines inhibit mitochondrial DNA outflow by downre-gulating the cGAS/STING signaling pathway. Thirdly, nanomedicines down-regulate TLR-3, thereby down-regulating the NF-kB signaling pathway. Fourthly, nanomedicines release TRPV1, thereby up-regulating CaMKII. These nanomedicines can ultimately induce M1 macrophages to form M2 macrophages, inhibit apoptosis, ferroptosis and inflammation, promote autophagy and eliminate ROS.

Figure 3

Nanomaterial-based DDSs treat OA by targeting synoviocytes. Nanomedicines modified with different ligands target synoviocytes through the corresponding receptors on synoviocytes to release functional drugs. Different nanomedicines regulate synoviocytes through different mechanisms. On the one hand, nanomedicines down-regulate the NF-kB signaling pathway, thereby reducing the production of ROS. On the other hand, nanomedicines up-regulate the AMPK/mTOR signaling pathway, thereby inhibiting TRPA1. These nanomedicines can down-regulate cartilage degradation factors and inflammatory factors such as MMP3, MMP-13, ADAMTS 5, COX-2, IL-1, IL-6 and TNF-α, and up-regulate cartilage synthesis factors and anti-inflammatory factors such as collegen, IL-4 and IL-10, and finally inhibit inflammation, promote autophagy and delay cartilage degradation.

Figure 4

Nanomaterial-based DDSs treat OA by targeting MSCs. Nanomedicines modified with different ligands target MSCs through the corresponding receptors on MSCs to release functional drugs. Different nanomedicines regulate MSCs through different mechanisms. Firstly, nanomedicines up-regulate the PI3K/AKT/mTOR signaling pathway. Secondly, nanomedicines promote glucose transport, thereby releasing more ATP. Thirdly, nanomedicines up-regulate HIF-1α. Fourthly, nanomedicines accelerate the release of Ca²⁺ from mitochondria, thereby promoting autophagy. Fifthly, nanomedicines promote the transcription of CBFβ -RUNX1. Sixthly, nanomedicines up-regulate Sox9, COL2A1 and Aggrecan. These nanomedicines eventually stimulate MCSs to differentiate into chondrocytes.

Figure 5

Nanomaterial-based DDSs treat OA by targeting chondrocytes. Nanomedicines modified with different ligands target chondrocytes through the corresponding receptors on chondrocytes to release functional drugs. Different nanomedicines regulate chondrocytes through different mechanisms. Nanomedicines down-regulate signaling pathways such as NF-kB, VEGF, Notch, β-catenin and Wnt3a, and up-regulate signaling pathways such as PI3K/AKT and AMPK. Nanomedicines also up-regulate cartilage degradation, apoptosis, inflammation and autophagy related genes, such as collagen, aggrecan, Bcl-2, IL-4, IL-10, and LC3, thereby inhibiting inflammation, apoptosis, extracellular matrix degradation and oxidative stress, and promoting autophagy.

Figure 6

Schematic illustration of cell membranes/EV-disguised nanomaterial-based DDSs. The cell membranes or EVs of functional cells such as macrophages, synoviocytes, MSCs and chondrocytes are extracted and encapsulated in nanomaterial-based DDSs. The nanomaterial-based DDSs are then injected into the knee joint of animals. The nanomaterial-based DDSs use biomolecules such as glycoprotein and integrin on the membrane surface to accurately identify the joint microenvironment, target functional cells and ultimately inhibit inflammation, extracellular matrix degradation, apoptosis and oxidative stress.