Communications Chemistry, Published online: 13 August 2026; doi:10.1038/s42004-026-02157-6L-type amino acid transporter 1 (LAT1) is a promising yet underexplored target against cancer, with current understanding of LAT1 inhibition being largely based on static structures of LAT1–inhibitor complexes. Here, the authors study molecular triggers of LAT1 conformational changes upon ligand binding through molecular dynamics simulations on LAT1-substrates and one inhibitor, JPH203, revealing alterations in hydration dynamics during transport and showing that JPH203 can block LAT1 not only in an outward-facing conformation but by stabilizing the inward-open state.

ジェイファーマ株式会社とUnipharが、胆道がんの新しい治療薬JPH203のグローバルな第3相試験を開始しました。これはがん治療の新たな選択肢となる可能性があります。

An IgG-opsonized carrier-free bilirubin/JPH203 nanoparticle has been successfully developed. This nanoparticle exhibits precise targeting capabilities and modulates macrophage M1-M2 polarization, resulting in the effective mitigation of inflammation and promotion of cartilage regeneration in rat models of osteoarthritis. This innovative strategy offers great promise for advancing osteoarthritis intervention and treatment in the field of nanomedicine. Abstract Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.