Phytochemical modulation of mTOR signaling: emerging nanotechnology-driven therapeutics for rheumatoid arthritis management.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by persistent synovial inflammation, cartilage degradation, and joint destruction. Central to RA pathogenesis is the mammalian target of the rapamycin (mTOR) signaling pathway, which regulates immune responses, cell proliferation, metabolism, and inflammation. Dysregulation of mTOR contributes to synovial hyperplasia, immune cell infiltration, and cytokine release. Although conventional therapies, including disease-modifying anti-rheumatic drugs and biologics, have improved clinical outcomes, their use is limited by cost, toxicity, and drug resistance. Phytochemicals-bioactive compounds derived from plants-have emerged as promising alternatives due to their immunomodulatory and anti-inflammatory properties, and their ability to target key molecular pathways, including mTOR. This review explores the role of phytochemicals such as curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, luteolin, celastrol, astragalus, and others in modulating the mTOR pathway and their therapeutic potential in RA. It provides mechanistic insights into how these compounds affect inflammatory signaling, immune cell activation, and the behavior of fibroblast-like synoviocytes. Challenges associated with poor solubility, low bioavailability, and rapid metabolism are discussed, alongside advances in nanoformulations that enhance targeted delivery and efficacy. Preclinical and emerging clinical evidence supports the role of phytochemicals, alone or in combination with conventional agents, in suppressing RA pathogenesis. Overall, phytochemicals targeting the mTOR pathway offer a safe, cost-effective, and multifunctional therapeutic strategy for RA management.