Intrinsic AIE Drug Nanocrystals Enable Imaging-Guided Orchitis Theranostics

ABSTRACT Acute orchitis and other inflammatory testicular diseases lack delivery platforms that enable label-free fluorescence tracking of drug distribution in inflamed testes. Here, we show that three clinically approved leukotriene receptor antagonists, namely Pranlukast, Zafirlukast, and Montelukast can be transformed into self-reporting, self-delivering, and self-therapeutic nanotheranostics. These drugs intrinsically possess aggregation-induced emission (AIE): extensive intermolecular halogen and hydrogen bonds simultaneously restrict intramolecular motion to generate bright solid-state fluorescence and drive spontaneous self-assembly into uniform, PEG-stabilized nanocrystals. Unlike conventional dye-labeled nanocarriers, in which dye leakage causes false signals, AIE fluorescence faithfully reports the aggregated nanocrystal state, enabling monitoring of drug integrity. Beyond their canonical anti-leukotriene activity, these drugs directly suppress NF-κB signaling and scavenge reactive oxygen species—mechanisms highly relevant to acute orchitis pathogenesis, which involves TLR4/MyD88/NF-κB activation and oxidative stress. In LPS-stimulated cells, the nanocrystals suppress NF-κB activation and scavenge reactive oxygen species. In a rat model of acute orchitis, AIE imaging reveals efficient testicular accumulation, which correlates with attenuated histopathological damage, restored oxidative stress balance, and downregulation of the TLR4/MyD88/NF-κB and PK2/PKR1 pathways, with no obvious adverse effects on the measured short-term reproductive indices (sperm morphology and testosterone levels) observed within the experimental timeframe. This strategy converts old drugs into minimal-excipient, self-monitoring AIE nanotheranostics for imaging-guided orchitis therapy.