This study aimed to develop a novel nanotechnological slow-release drug delivery platform based on hyaluronic acid Microsponge (MSP) for the subcutaneous administration of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). RA is a chronic autoimmune disease characterized by joint inflammation and damage, while MTX is a common disease-modifying antirheumatic drug (DMARD), the conventional use of which is limited by adverse effects and the lack of release control. In this work, MSP were synthesized as freeze-dried powder to increase their stability and allow for a facile reconstitution prior to administration and precise MTX dosing. These MSP exhibited stable, rounded shapes, with a signature open porosity structure, and achieved a high MTX loading efficiency, with a slow release after injection. Our drug release studies demonstrated indeed an initial burst, followed by sustained release over a month. Remarkably, by means of a (collagen induced - CIA) rat model of RA, the MTX-loaded MSP almost doubled the therapeutic efficacy, by significantly reducing arthritic scores compared to controls. The pre-clinical study was replicated twice to confirm this marked improvement in performance and the safety profile of MSP. The results show the potential of MSP mediated therapy to enhance MTX efficacy in RA treatment by enabling sustained slow-release while minimizing side effects. This study therefore suggests that the MSP platform may be considered in clinical practice for improving the MTX delivery in RA therapy.