Chiral Nanoparticles Suppress Inflammatory Infiltration to Promote Extracellular Matrix Remodeling for Ectopia Lentis Therapy

ABSTRACT Chirality, a fundamental geometric property of matter, plays a pivotal role in biological systems by mediating stereoselective molecular interactions and cellular regulation. Inspired by this principle, chiral nanoparticles have emerged as promising candidates for immunomodulation in inflammation‐related diseases. However, whether and how their chiral cues regulate extracellular matrix (ECM) remodeling remains largely unexplored. Herein, we report the design of L‐cysteine‐configured polyurethane nanoparticles (L‐CN) through covalent grafting of naturally chiral L‐cysteine, and demonstrate their therapeutic potential for ectopia lentis (EL) — a disease characterized by progressive zonular fiber degeneration. Mechanistically, L‐CN suppresses the nuclear factor kappa B signaling pathway in M 1 macrophages through the anti‐inflammatory activity of L‐cysteine, thereby attenuating inflammatory responses and reducing ECM degradation in vitro. In an EL rat model, it facilitates CD163 + M 2 macrophages polarization, leading to the restoration of FBN1 and MFAP2 expression in zonular fibers and ultimately promoting zonular fiber reconstruction. Overall, this study establishes a chirality‐mediated immunomodulatory strategy for ECM reconstruction and provides a minimally invasive therapeutic approach for EL and potentially other matrix‐degenerative disorders.