Rheumatoid arthritis (RA) is a debilitating, chronic autoimmune disorder that impacts approximately 0.5–1 % of the global population, imposing substantial socioeconomic burdens through healthcare expenditures, disability, and reduced productivity [1], [2]. The disease is characterized by persistent synovial inflammation, progressive joint destruction, and systemic complications, disproportionately affecting women (3:1 ratio) with typical onset between 40–60 years of age, though it can manifest at any time [3]. If left untreated, irreversible joint damage often occurs within two years, underscoring the necessity of early intervention to preserve patient quality of life and mitigate mortality risks [4]. Significant advancements in pharmacotherapy have notably enhanced RA management. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief but lack disease-modifying capabilities and carry risks of gastrointestinal, cardiovascular, and renal toxicities with prolonged use [5]. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, achieve remission in many patients but fail in 30–40 % and pose risks like hepatotoxicity and infections [6], [7]. Biologic agents, including tumor necrosis factor-alpha (TNF-α) inhibitors, have revolutionized care by specifically targeting key cytokines. Meta-analyses of clinical trials (e.g., from the American College of Rheumatology) show 40–50 % remission rates and considerable reductions in disability [8]. While these therapies improve patient outcomes, challenges persist: high costs restrict access, infection and malignancy risks increase, and off-target effects often require higher doses [9], [10]. Systemic delivery frequently results in suboptimal joint concentrations, while immunogenicity can lead to treatment failure. Crucially, these approaches slow joint damage but rarely reverse it [11]. To bridge these therapeutic gaps, and building upon the successes of existing biologics, biological macromolecules emerge as versatile platforms for next-generation RA therapeutics. These biocompatible entities, including proteins, peptides, polysaccharides (e.g., hyaluronic acid (HA)), nucleic acids, exosomes, and nanocellulose, facilitate targeted immunomodulation, enhanced delivery, and tissue regeneration [12]. For example, HA systems provide joint lubrication and CD44-targeted delivery, while mesenchymal stem cell-derived exosomes promote anti-inflammatory macrophage polarization in preclinical models [13]. Functionalization strategies, such as ligand conjugation, improve macromolecule stability and enhance synovial accumulation, with early animal studies showing substantial reductions in inflammation and damage (e.g., up to 6.5-fold with HA-nanohydrogels) [14]. This review focuses on promising macromolecule-driven strategies across drug delivery, regenerative medicine, and orthopedic repair, categorizing the evidence by stage (preclinical vs. emerging clinical) [15]. It balances the proven anti-inflammatory impacts of biologics with the innovative potential for regeneration, analyzing underlying mechanisms, preclinical/clinical data, and translational hurdles to guide RA management toward holistic, curative outcomes.