Robust drug bioavailability and safety for rheumatoid arthritis therapy using D-amino acids-based supramolecular hydrogels

Long-term use of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) shows clinical benefits for rheumatoid arthritis (RA) treatment. However, there are growing concerns over the adverse effects of systemic drug administration. Therefore, a strategy that can enhance drug bioavailability while minimizing side effects is urgently needed, but remains a challenge in RA therapy. To this end, here we conjugated MTX with a supramolecular self-assembling hydrogel composed of d-amino acids with a sequence of G(D)F(D)F(D)Y. It was shown that MTX-G(D)F(D)F(D)Y hydrogels exhibited a favorable drug selectivity behavior that they increased MTX toxicity toward RA synoviocytes, but reduce toxicity toward normal cells. Moreover, MTX-G(D)F(D)F(D)Y hydrogels not only effectively inhibited the proliferation and migration of RA synoviocytes, but also inhibited the polarization of proinflammatory M1 type macrophages to reduce inflammation. After intra-articularly injected the hydrogels into the joints of adjuvant induced arthritis (AIA) mice, we found that MTX-G(D)F(D)F(D)Y hydrogels significantly alleviated RA syndromes of joint swelling and fever compared to L-configuration MTX-GFFY hydrogels and free MTX. Furthermore, MTX-G(D)F(D)F(D)Y hydrogels successfully protected cartilage though inhibiting synovial invasion and inflammation without causing systematic side effects. Therefore, d-amino acids supramolecular hydrogels can serve as an efficient and safe drug delivery system, showing a promising potential to improve RA therapy.