Biological macromolecule-driven therapeutics in rheumatoid arthritis: Integrating drug delivery, regenerative medicine, and orthopedic repair.

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5-1 % of the global population, leading to joint destruction, disability, and high socioeconomic costs. While conventional therapies like DMARDs and biologics have improved outcomes, limitations persist, including incomplete efficacy, systemic toxicities, and minimal tissue regeneration. This review evaluates the therapeutic potential of biological macromolecules (e.g., proteins, polysaccharides, nucleic acids, exosomes) in RA management across drug delivery, regenerative medicine, and orthopedic repair, highlighting their inherent advantages over traditional approaches. Macromolecules offer superior biocompatibility and multifunctionality, enabling highly targeted immunomodulation, controlled drug release, and effective tissue regeneration. Preclinical studies using engineered systems such as HA-functionalized nanoparticles and exosome-based scaffolds demonstrate enhanced joint targeting and significant reductions in inflammation. Early clinical data suggest improved patient outcomes, including better remission rates and joint function, when these systems are integrated with existing biologics. Biological macromolecules represent a promising shift toward regenerative RA therapies, addressing unmet needs in disease modification and structural repair. Challenges concerning manufacturing scalability and immunogenicity must be overcome for clinical translation, potentially transforming RA from symptomatic control to curative strategies.