Harnessing Tissue-derived Extracellular Vesicles for Osteoarthritis Theranostics

Abstract

Osteoarthritis (OA) is a prevalent chronic whole-joint disease characterized by low-grade systemic inflammation, degeneration of joint-related tissues such as articular cartilage, and alteration of bone structures that can eventually lead to disability. Emerging evidence has indicated that synovium or articular cartilage-secreted extracellular vesicles (EVs) contribute to OA pathogenesis and physiology, including transporting and enhancing the production of inflammatory mediators and cartilage degrading proteinases. Bioactive components of EVs are known to play a role in OA include microRNA, long non-coding RNA, and proteins. Thus, OA tissues-derived EVs can be used in combination with advanced nanomaterial-based biosensors for the diagnostic assessment of OA progression. Alternatively, mesenchymal stem cell- or platelet-rich plasma-derived EVs (MSC-EVs or PRP-EVs) have high therapeutic value for treating OA, such as suppressing the inflammatory immune microenvironment, which is often enriched by pro-inflammatory immune cells and cytokines that reduce chondrocytes apoptosis. Moreover, those EVs can be modified or incorporated into biomaterials for enhanced targeting and prolonged retention to treat OA effectively. In this review, we explore recently reported OA-related pathological biomarkers from OA joint tissue-derived EVs and discuss the possibility of current biosensors for detecting EVs and EV-related OA biomarkers. We summarize the applications of MSC-EVs and PRP-EVs and discuss their limitations for cartilage regeneration and alleviating OA symptoms. Additionally, we identify advanced therapeutic strategies, including engineered EVs and applying biomaterials to increase the efficacy of EV-based OA therapies. Finally, we provide our perspective on the future of EV-related diagnosis and therapeutic potential for OA treatment.

Keywords: Biomaterials; Biosensors; Controlled-release; Extracellular vesicles; Osteoarthritis.

Figure 1

Macroscopic and microscopic illustration of osteoarthritis (OA). (A) Knee OA at four different stages can be evaluated by K-L scores, including “normal” at stage 1. Only cartilage degradation is shown for illustration simplicity instead of the whole-joint damages. (B) Microscopic exploration of normal and osteoarthritic chondrocytes interacting with other cell types through cell-cell communication (EV secretion) at stage 4 with possible biological outcomes. The synovial fluid-derived EVs can be extracted for OA diagnosis. Green/red curve arrows indicate cells secreting EVs with bioactive molecules that potentially are chondro-protective/chondro-destructive. Osteoarthritic chondrocytes may also secret EVs to stimulate inflammasome activation of cells in synovial space, including macrophages.

Figure 2

Overview of the process and principles of biosensors to detect EVs and OA biomarkers in EVs. (A) OA site-derived EV proteins and nucleic acids can be conventionally detected by ELISA-based and qPCR-based methods, respectively. (B) Recent advances in nanotechnology develop many rapid and cost-effective biosensors for detecting EVs and EV contents through (C) various techniques. (D) EVs can be probed by (i) fluorescence-based system on CD63-targeting Cy3-conjugated aptamer, which is initially quenched by MXene nanosheets and recovers the fluorescent signal upon binding to EVs in the solution ; (ii) SPR-based system with EV surface protein-specific antibodies to capture EVs that cause the evanescent surface plasmon wave at the sensor surface to generate differential optical signals for distinguishing normal or diseased EVs ; and (iii) SERS-based system to amplify the Raman profile of specific surface protein of EVs for distinguishing normal or diseased EVs . (E) EV contents can also be detected by biosensors, such as the use of an SPR-based system consisting of specific antibodies immobilized on gold nanoparticles/optic fiber sensor to detect OA-related markers (such as TNF-α) from human knee SF . The figures are reprinted and re-arranged with permission from Ref. -. Copyright American chemical society. (2018), Royal Society of Chemistry (2013), and SpringerLink. (2015).

Figure 3

Schematic representation of engineering EVs for cargo delivery by various types of strategies for OA. (A) Chemical engineering strategies for the incorporation of (i) hydrophobic drugs, (ii) hydrophilic drugs, (iii) proteins/nucleic acids, and (iv) targeting moieties into EVs. Genetic/biological engineering strategies for (v) nucleic acids and (vi) targeting motifs overexpression in EVs. Multiple strategies may be combined to optimize therapeutic efficacy. (B) Genetically/chemically engineered MSCs-derived EVs can be used for targeting and repolarizing activated macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory) to treat OA as the recent novel therapeutic approach. (C) Genetically engineering synovial fluid MSCs-derived EVs to target chondrocytes for OA . The figures are reprinted with permission from Ref. . Copyright American chemical society (2020).

Figure 4

Summary of EV-biomaterials for cartilage tissue engineering or treatment of OA. Biomaterials for OA include implanted biomaterials and intra-articularly injected biomaterials into joints induced with OA (e.g., DMM or osteochondral defects). Biomaterials are generated from natural polymers/materials such as decellularized cartilage tissue, hyaluronic acid, gelatin, collagen, chitosan, nanoclay, or even synthetic polymers, including PEG. Studies feature various strategies to modulate biomaterial tunability and EV retention and releases, such as chemical crosslinking, chemical modification of natural polymers to enable photocrosslinking or thermoreversibility, and even synthetic thermoresponsive triblock copolymer that forms micelles at room temperature.