Bridging Pharmacology and Nanotechnology: Mechanistic Insights into Traditional Chinese Medicine-Based Nanodelivery Systems for Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Importantly, this review emphasizes the mechanistic linkage among TCM active compounds, nanocarrier design, and rheumatoid arthritis (RA) signaling pathways. By integrating carrier-mediated targeting, microenvironment-responsive release, and pathway-specific modulation (e.g. NF-κB, JAK/STAT, MAPK, Nrf2, and NLRP3), TCM-based nanodelivery systems are shown to remodel the synovial immune microenvironment, enhance intracellular drug accumulation in macrophages and fibroblast-like synoviocytes, and amplify multi-level anti-inflammatory and immunomodulatory effects. This mechanistic integration provides a framework for rational design of next-generation nanomedicines for RA therapy. Methods: Recent studies were systematically analyzed to categorize lipid-based, polymeric, inorganic, biomimetic, and stimuli-responsive nanocarriers, with emphasis on formulation strategies, pharmacokinetic/pharmacodynamic enhancement, and mechanistic modulation of inflammatory and immune pathways. Results: Nanodelivery systems not only improve drug solubility, stability, and lesion accumulation, but also reshape the interaction between TCM compounds and RA-associated signaling networks. Distinct classes of phytochemicals exhibit characteristic mechanistic profiles: triterpenoids (e.g. celastrol, triptolide) primarily suppress NF-κB, proteasome activity, and osteoclastogenesis, whereas flavonoids (e.g. baicalin, icariin, curcumin) preferentially regulate NLRP3 inflammasome activation, Th17/Treg balance, and antioxidant pathways. Nanocarrier-mediated delivery further amplifies these effects through targeted release, immune cell modulation, and microenvironment-responsive activation. Conclusion: The integration of nanotechnology with TCM pharmacology provides mechanistic synergy by coupling material-based targeting with pathway-specific regulation. This dual modulation represents a key advantage over conventional therapies and supports the rational design of mechanism-guided TCM-based nanomedicines for RA.