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

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 M1 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+ M2 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.