BILIRUBIN NANOMEDICINES: PRECLINICAL ADVANCES, MECHANISTIC INSIGHTS, AND EMERGING TRANSLATIONAL PROSPECTS

Bilirubin, a natural endogenous antioxidant and potent free radical scavenger, has emerged as a remarkably versatile therapeutic agent in the era of nanomedicine. Historically viewed primarily as a marker of hepatic dysfunction, bilirubin is now recognized for its pleiotropic cytoprotective properties including anti-oxidative, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. However, its clinical application has been hampered by poor aqueous solubility, photosensitivity, and narrow therapeutic index. Nanoparticle-based delivery systems have effectively addressed these limitations, enabling controlled delivery, enhanced bioavailability, targeted tissue distribution, and stimuli-responsive release of bilirubin. This comprehensive review systematically discusses the physico-chemical properties of bilirubin, the rationale for nanomedicine-based formulations, diverse nanoparticle platforms including self-assembled bilirubin nanoparticles, PEGylated conjugates, lipid nanoparticles, albumin-bilirubin complexes, chitosan carriers, quantum dots, and metal-based hybrid systems. We critically evaluate the mechanisms of therapeutic action, including reactive oxygen species (ROS) scavenging, NF-κB pathway suppression, heme oxygenase-1 (HO-1) activation, complement inhibition, ferroptosis regulation, and immune checkpoint modulation. We further review recent preclinical advances across inflammatory bowel disease, cancer immunotherapy, neonatal jaundice, liver diseases, neurological disorders, cardiovascular diseases, and acute lung injury. The translational landscape, including Phase I clinical studies, is examined alongside current challenges in manufacturing scalability, long-term stability, immunogenicity, and regulatory pathways. This review aims to serve as a consolidated scientific reference for researchers and clinicians advancing bilirubin nanomedicines toward clinical translation.