Targeted nanocarriers integrating photodynamic and photothermal therapy: a paradigm shift in rheumatoid arthritis treatment.

Rheumatoid Arthritis (RA) is a crippling autoimmune disease characterized by gradual cartilage loss, bone degeneration, and persistent joint inflammation. Widespread adverse effects and ineffective drug distribution hamper the traditional treatment modalities. Recent progress in RA treatment has been advanced by nanocarrier-based phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT). These therapies work by inducing necrosis or apoptosis in inflammatory cells through the generation of reactive oxygen species via PDT or localized heat production by PTT. This also leads to a reduction in pro-inflammatory cytokines and modulates macrophage polarization (M1 to M2). This dual approach shows enhanced efficacy by targeting inflammatory cytokines while preserving healthy tissue function, providing site-specific delivery, and improving bioavailability. Preclinical investigations have demonstrated that functionalized nanocarriers for targeting macrophages and synovial fibroblasts show improved drug delivery and therapeutic outcomes. While clinical trials of PDT in refractory RA patients have shown promising results in targeting synovial hyperplasia and inflammatory markers with minimal side effects, the challenges of limited light penetration, hypoxic joint microenvironments, and poor target specificity reduce the efficacy of PDT. This review focuses on multifunctional nanoplatforms that integrate PDT and PTT therapies with nanocarriers, advanced light delivery systems, and phototherapy devices to optimise RA management. These innovations aim to enhance therapeutic precision, reduce symptoms, and improve patient adherence. It also explores cutting-edge advancements in RA treatment strategies, addresses current limitations, and proposes future research directions to bridge the gap between preclinical success and clinical application.