A thermoresponsive magnetic nanocarrier with the DNA-mimetic base pairing-guided controlled release of methotrexate in the treatment of rheumatoid arthritis

Controlled drug delivery systems not only augment the therapeutic efficacy of drugs but also mitigate their adverse effects. Methotrexate (MTX) is a prominent first-line therapeutic agent in the management of rheumatoid arthritis (RA), yet it is characterized by its limited aqueous solubility, pronounced hemolytic activity, and propensity for off-target binding, which collectively contribute to its significant toxicity profile. To address these issues, a temperature-responsive controlled release system for MTX based on the analogous base pairing rule was designed for the RA treatment. Magnetic ferroferric oxide nanoparticles (Fe₃O₄ NPs) coated with polydopamine (PDA) were modified with thymidine-1-acetic acid (TAA) to prepare nanocarrier (FPT NPs). Furthermore, the thymine molecules within the FPT NPs possessed the strong ability to specifically bind with the pteridine structure present in MTX, thereby enabling the fabrication of a nanomedicine (designated as FPT-MTX NPs) through the base pairing rule. Under the influence of an applied magnetic field, the FPT-MTX NPs demonstrated a remarkable capacity for precisely targeting the joint tissue in a mouse model of RA. Analogous to DNA, where double-strand breaks occurred due to heating-induced disruption of base pairing, MTX was released from FPT-MTX NPs following near-infrared irradiation-induced light-to-heat conversion. This mechanism facilitated the achievement of satisfactory therapeutic outcomes in the RA treatment.