Secreted Protein Acidic and Rich in Cysteine Mediated Biomimetic Delivery of Methotrexate by Albumin-Based Nanomedicines for Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Despite considerable advances in clinical treatment of RA, suboptimal response to therapy and treatment discontinuation are still unresolved challenges due to systemic toxicity. It is of crucial importance to actively target and deliver therapeutic agents to inflamed joints in order to promote in situ activity and decrease systemic toxicity. In this study, we found that SPARC (secreted protein acidic and rich in cysteine) was overexpressed in the synovial fluid and synovium of RA patients as well as mice with collagen-induced arthritis (CIA), which has been scarcely reported. Building upon the SPARC signature of RA joint microenvironment and the intrinsic high affinity of SPARC for albumin, we fabricated methotrexate-loaded human serum albumin nanomedicines (MTX@HSA NMs) and explored them as biomimetic drug delivery systems for RA therapy. Upon intravenous injection of chlorin e6-labeled MTX@HSA NMs into CIA mice, the fluorescence/magnetic resonance dual-modal imaging revealed higher accumulations and longer retention of MTX@HSA NMs in inflamed joints with respect to free MTX molecules. In vivo therapeutic evaluations suggested that the MTX@HSA NMs were able to attenuate the progression of RA with better efficacy and fewer side effects even at half  dose of administrated MTX in comparison with free MTX. By unraveling the mechanism driving the efficient accumulation of MTX@HSA NMs in RA joints and showing their ability to improve the safety and therapeutic efficacy of MTX, our work sheds light on the development of innovative anti-RA nanomedicines with a strong potential for clinical translation.