Structurally Resilient Peptide Assembly Regulates Pathogenic Galectin-10 Crystallization To Mitigate Crystallopathy Inflammation

Pathogenic protein crystallization <i>in vivo</i> triggers multifactorial inflammatory cascades that ultimately lead to irreversible tissue damage, representing an unmet therapeutic challenge. Here we report ISQ, a novel self-assembling peptide that specifically targets galectin-10 (Gal-10) crystallization─a key pathological driver of airway inflammation, where Gal-10 crystal deposition activates interleukin-1β (IL-1β)-dependent pathways and promotes neutrophilic inflammation. ISQ exhibits dual functionality: it not only binds Gal-10 with nanomolar affinity (<i>K</i>_D = 2.1 nM) to dissolve preformed crystals <i>in vitro</i>, but also spontaneously self-assembles into stable nanostructures with structural resilience that maintain target recognition even after thermal denaturation, demonstrating superior robustness compared to antibodies. In a Gal-10 crystal-induced murine model, intratracheal administration of ISQ assemblies significantly attenuated airway inflammation, reducing both proinflammatory cytokine production and neutrophil infiltration. The therapeutic efficacy was further confirmed in primary airway epithelial cells derived from patients with Gal-10 crystallopathies. Collectively, these findings establish ISQ as a first-in-class, self-assembling peptide therapeutic that disrupts pathogenic protein crystallization, offering a promising treatment strategy for crystallopathy inflammation currently lacking effective interventions.