Recent advances in bilirubin photoisomerization and photodegradation: in vitro and in vivo evidence for jaundice treatment.

Neonatal jaundice, characterized by unconjugated hyperbilirubinemia, remains one of the most prevalent conditions affecting both term and preterm neonates. Elevated bilirubin levels may progress to acute bilirubin encephalopathy or kernicterus, resulting in irreversible neurological damage and increased mortality. Phototherapy is the standard treatment for neonatal hyperbilirubinemia, promoting bilirubin elimination through photoisomerization and photodegradation pathways that generate more water-soluble products, bypassing hepatic metabolism. Over the past decades, significant advances have been made in light-based technologies aimed at improving the efficiency of bilirubin photoconversion. In particular, wavelength optimization, high-intensity light-emitting diodes (LEDs) systems, and emerging photonic and nanomaterial-based approaches have been explored to enhance therapeutic outcomes. In this review, a structured literature search was conducted using the Web of Science database, covering the past 20 years, to analyze recent developments in bilirubin photoisomerization and photodegradation (in vitro and in vivo studies). The results demonstrate that photodegradation efficiency is strongly dependent on wavelength, with optimal performance observed in the blue-green region (490-500 nm), where reduced bilirubin half-life and increased lumirubin formation are reported. Furthermore, high-intensity LED systems generally provide higher irradiance and more favorable degradation kinetics than conventional light sources, although direct comparison among studies remains limited by differences in irradiation geometry, exposure time, bilirubin concentration, and experimental models. Emerging strategies, including optoacoustic monitoring, fluorescence-based theragnostic systems, and nanomaterial-assisted photocatalysis (e.g., ZnO nanoparticles, Au nanocomposites, and functionalized Fe₃O₄ systems), have demonstrated enhanced bilirubin degradation and offer new perspectives for both therapeutic optimization and real-time monitoring. However, most of these approaches remain at the proof-of-concept or preclinical stage, and their clinical translation requires validation of biocompatibility, selectivity, reproducibility, scalability, and neonatal safety. Optical and point-of-care sensing technologies may enable individualized adjustment of phototherapy, but their performance must be validated under clinically relevant conditions and across different gestational ages, skin characteristics, and bilirubin concentrations. Additionally, bilirubin degradation is not solely a detoxification process, as photooxidation products may exhibit biological activity with potential clinical implications. Future studies should therefore focus on optimizing irradiation parameters (wavelength, irradiance, and exposure time), elucidating photochemical pathways, and characterizing degradation products, while correlating these findings with clinical outcomes. Standardized experimental and clinical protocols will also be essential to compare technologies and determine whether improved photochemical performance translates into faster bilirubin reduction, shorter treatment duration, and fewer adverse effects. Such integration may support the development of more efficient, safer, and personalized phototherapy strategies in neonatal care.