Nanotherapy for rheumatoid arthritis: A ceria nanoparticle–mesenchymal stem cell nanovesicle hybrid system

Taeghwan Hyeon of the Institute for Basic Science (IBS) in Korea, Youngmee Jung of the Korea Institute of Science and Technology (KIST), and Byung-Soo Kim of Seoul National University, in collaboration with other researchers, recently devised a hybrid system involving ceria nanoparticles (Ce NPs) attached to mesenchymal stem cell nanovesicles to target the various pathogenic factors associated with rheumatoid arthritis (RA). This study demonstrates the efficacy of the therapy in treating and preventing RA through symptom relief and the induction of regulatory T (Treg) cells in a collagen-induced arthritis (CIA) mouse model. The findings were published in the prestigious journal, Nature Nanotechnology.¹

RA is characterized by inflammatory autoimmune responses that lead to the loss of immune tolerance, synovial inflammation, and tissue damage, ultimately causing systemic and persistent functional limitations.² The precise etiology of RA remains uncertain; however, it is established that the aforementioned factors can synergistically contribute to a self-perpetuating cycle that significantly influences the onset and progression of the disease. The standard initial approach to managing RA involves the administration of anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and biologics, albeit these pharmacological interventions primarily target symptom alleviation. While this method may provide short-term relief, it is crucial to acknowledge the potential adverse effects that may arise from prolonged drug use. As such, the optimal approach to treating RA should prioritize the restoration of normal immune function and the prompt suppression of inflammatory reactions and associated symptoms.³

Numerous studies have demonstrated the effective modulation of innate immunity through the promotion of anti-inflammatory M2 macrophages. Nevertheless, RA represents a chronic autoimmune condition that requires a more holistic strategy to restore immune function within both the innate and adaptive immune responses. Failing to achieve this objective necessitates the continued administration of palliative drugs, underscoring the critical need for a multifaceted intervention system capable of targeting numerous pathogenic factors to ensure comprehensive treatment of RA.⁴

The Ce–mesenchymal stem cell nanovesicle (MSCNV) system is engineered to capitalize on the antioxidant properties of Ce NPs to neutralize reactive oxygen species (ROS), a pivotal pathogenic factor in RA, and to induce a phenotypic shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages. Simultaneously, MSCNVs within the hybrid system protect chondrocytes and deliver immunomodulatory cytokines, fostering a tolerogenic phenotype in dendritic cells (DCs) and the subsequent induction of Treg cells. This dual action targets the intricate interplay of pathogenic factors in RA, providing immediate relief and long-term disease modification.

The development of the Ce–MSCNV hybrid system represents a paradigm shift in RA treatment by simultaneously targeting multiple pathogenic factors. RA, a disease affecting millions worldwide, is currently managed primarily through symptom-focused treatments. The Ce–MSCNV system exemplifies the potential of nanotechnology in immunomodulatory therapy. By conjugating Ce NPs with MSCNVs, the hybrid system synergizes the ROS-scavenging activity of Ce NPs to reduce inflammation and the immunomodulatory potential of MSCNVs to restore immune balance. This synergistic approach has been demonstrated to effectively treat and prevent RA in a CIA mouse model, presenting a promising alternative to conventional treatments (Figure 1).

The Ce–MSCNVs' immunomodulatory effects are multifaceted. Ce NPs, with their inherent antioxidant capabilities, neutralize excess ROS, mitigating synovial inflammation. Meanwhile, MSCNVs protect chondrocytes and modulate the immune environment by inducing tolerogenic DCs, which in turn promote Treg cell differentiation. This rebalancing of the T-helper type 17 (TH17)/Treg cell ratio is essential for restoring immune tolerance in RA. The therapeutic efficacy of Ce–MSCNVs was evaluated in a CIA mouse model, where treatment led to significant improvements in clinical scores, reduced paw swelling and hyperthermia, and decreased hyperalgesia. Histological analysis revealed preservation of cartilage structure and diminished synovitis and angiogenesis in treated animals. Furthermore, the treatment facilitated a sustained restoration of the immune system, evidenced by the induction of Treg cells and the rebalance of TH17/Treg cell ratios.

The Ce–MSCNV hybrid system represents a revolutionary advance in RA treatment, seamlessly combining anti-inflammatory and immunomodulatory functions. This research underscores the unmatched potential of nanotechnology in crafting multifunctional therapeutics capable of addressing the intricate and multifaceted pathogenesis of RA. The Ce–MSCNV system distinguishes itself by surpassing the constraints of conventional, single-modality treatments, offering instead a nuanced, multifactorial intervention strategy. Unlike traditional therapeutics that focus on symptom relief through individual drugs, the Ce–MSCNV system presents a holistic treatment protocol. It harmonizes the antioxidant prowess of CeNPs with the immunomodulatory capabilities of mesenchymal stem cell nanovesicles. This dual mechanism not only provides swift relief from inflammatory symptoms but also fosters a return to immune balance by recalibrating the T cell subset equilibrium, thereby supporting long-term immune system stability. However, alongside the therapeutic promise of the Ce–MSCNV system, there are pragmatic concerns that necessitate attention. Issues such as production costs, system stability, and scalability for clinical application must be rigorously examined. It is imperative for future studies to surmount these obstacles to affirm the Ce–MSCNV system as a practical and economically viable RA treatment option. This study accentuates the value of an approach that concurrently manages symptomatic relief and the root cause of immune misregulation, thereby paving the way for future exploration and clinical deployment in RA and a spectrum of autoimmune conditions. While the Ce–MSCNV system is replete with potential for transforming RA treatment, further investigation is essential to tackle questions of safety, efficacy, applicability, and fiscal sustainability, ensuring its successful translation from bench to bedside.

Jing Zheng performed the study concept and design, Kai Zhou handled the development of the writing and review, and Xinlong He provided the revision of the paper. All authors read and approved the final paper.

The authors declare no conflicts of interest.

Not applicable.