Abstract
Rheumatoid arthritis (RA) progresses through distinct pathophysiological states, transitioning from acute inflammatory phases with largely reversible tissue damage to chronic destructive stages characterized by irreversible structural alterations. Current therapeutic approaches largely employ uniform interventions without accounting for this disease heterogeneity, potentially compromising treatment efficacy. Dysregulated reactive oxygen species metabolism represents a mechanistic thread connecting RA stages. Acute inflammation is characterized by intense oxidative bursts, whereas chronic RA exhibits persistent oxidative stress, establishing a stage-dependent rationale for enzyme-based intervention. However, natural antioxidant enzymes are rapidly inactivated within the harsh inflammatory microenvironment, which is defined by acidic conditions and elevated proteolytic activity. Nanozymes are nanomaterials with enzyme-like catalytic activities, which overcome these limitations through enhanced environmental stability, tunable catalytic activity, and multifunctional integration. In contrast to prior nanozyme reviews that primarily organized discussions by material types or catalytic mechanisms, this review adopts a stage-oriented framework that aligns therapeutic strategies with the temporal evolution of RA pathophysiology. During acute inflammatory phases, nanozyme platforms integrate catalytic performance optimization, targeted delivery mechanisms, and synergistic anti-inflammatory interventions to rapidly neutralize oxidative stress and disrupt inflammatory cascades before irreversible damage occurs. In chronic destructive phases, therapeutic approaches combine sustained catalytic activity, precision targeting of established pathological structures, and multifunctional integration to concurrently suppress residual inflammation and promote tissue regeneration. This review compares nanozyme therapeutics with established RA treatments, including disease-modifying antirheumatic drugs and biological agents, to clarify their potential clinical positioning. Key challenges for clinical translation include long-term safety characterization; pharmacokinetic evaluation, particularly for intra-articular delivery; regulatory pathway development; and manufacturing scalability. Overall, this review establishes a stage-oriented nanozyme therapeutic framework aligned with RA progression patterns and provides translational guidance for developing nanozyme therapeutics tailored to individual pathological characteristics in RA management.