Nanomedicines for improved targetability to inflamed synovium for treatment of rheumatoid arthritis: Multi-functionalization as an emerging strategy to optimize therapeutic efficacy.

Owing to its intricate autoimmune pathophysiology and significant risks of progression to other rheumatic co-morbidities (i.e., osteoporosis and osteoarthritis), a plausible therapeutic regimen is mandatory for early-stage management of rheumatoid arthritis (RA). Nevertheless, the conventional therapeutic agents particularly the corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) have shown grander success in the treatment of RA; however, long-term use of these agents is also associated with serious adverse events. To combat these issues and optimize therapeutic efficacy, nanotechnology-based interventions have been emerged as viable option. While, nanomedicines signposted superiority over the conventional pharmacological moieties; there are still many pharmacokinetic and pharmacodynamic challenges to nanomedicines following their intravenous or intra-articular administration. To circumvent these challenges, significant adaptations such as PEGylation, surface conjugation of targeting ligand(s), and site- responsive behavior (i.e., pH-, biochemical-, or thermal-responsiveness) have been implemented. Besides, multi-functionalization of nanomedicines has been emerging as an exceptional strategy to overcome pharmacokinetic challenges, improve targetability to inflamed synovium, maximise internalisation into the activated macrophages, and improved therapeutic outcomes for treatment of RA. Therefore, this review aims to conceptualize and recapitulate the substantial evidences regarding the pharmacokinetic and pharmacodynamic superiority of multi-functionalized nanomedicines over the naked nanomedicines for site-selective targeting to inflamed synovium and rational treatment of RA and other rheumatic co-morbidities. Pharmaceutical sustainability of the multi-functionalized nanomedicines for improved biocompatibility, profound interaction with the targeting tissue/cells/sub-cellular domain, and diminished systemic toxicity has also been pondered.