Gold-based therapeutics in rheumatoid arthritis: from conventional chrysotherapy to gold nanoclusters

Gold-based therapeutics were among the earliest disease-modifying treatments for rheumatoid arthritis (RA), with Au(I)-containing compounds such as sodium aurothiomalate and auranofin demonstrating significant anti-inflammatory and immunomodulatory activity. Despite their therapeutic efficacy, widespread clinical adoption was hindered by systemic toxicity, poor pharmacokinetics, and limited control over biodistribution. Recent advances in nanotechnology have renewed interest in gold-based therapeutics through the development of atomically precise gold nanoclusters (AuNCs). Typically smaller than 3 nm, AuNCs exhibit unique size-dependent physicochemical and biological properties, including atomically defined structures, tunable surface chemistry, improved biocompatibility, and efficient renal clearance. Emerging evidence demonstrates that AuNCs can modulate inflammatory pathways by regulating oxidative stress, suppressing proinflammatory cytokine production, and selectively interacting with immune cells. This review traces the evolution of gold-based therapeutics from classical Au(I)-based drugs to atomically precise gold nanoclusters, highlighting the conceptual bridge between historical chrysotherapy and modern nanomedicine. While providing historical context, this review primarily covers studies published from the mid-1990s to the present, with particular emphasis on recent advances in AuNC design, their anti-inflammatory mechanisms, therapeutic applications in rheumatoid arthritis, and the structural features that underpin their biological activity and therapeutic potential.