Bilirubin nanotechnology: An innovative approach in biomedicine

Bilirubin, a product of heme catabolism, is toxic at elevated concentrations (>250–300 μM in blood serum), whereas at therapeutic concentrations (∼20–200 μM) exerts potent antioxidant, anti-inflammatory, immunomodulatory, cytoprotective and neuroprotective effects. Despite the therapeutic potential, its use in clinical practice is hampered by poor aqueous solubility, instability, and rapid metabolism. Nanotechnology overcomes these limitations and additionally imparts to bilirubin the advantages characteristic of nanopreparations: targeted action on the desired organ/tissue, increased therapeutic efficacy by delaying drug elimination from the body, improved transportation over biological barriers, the ability to combine therapeutic and diagnostic properties in a single agent. The review analyses the chemical synthesis, therapeutic mechanisms, and preclinical applications of nanosystems comprising bilirubin. In particular, nanostructures obtained by the covalent binding of bilirubin to macromolecules, bilirubin encapsulation in nanocarriers, bilirubin conjugation with metal nanoparticles and nanofunctionalization of inorganic compounds are considered; the data on the therapeutic trials of nanobilirubin are summarized. While studies on animal models and in vitro systems demonstrate improved biodistribution, reduced toxicity, and enhanced efficacy, no clinical trials to date have validated nanobilirubin formulations. Key barriers may include unresolved challenges in scalable synthesis, long-term biocompatibility, reproducible dosing of nanoformulations. Hence, further development of nanotherapeutic bilirubin agents for clinical practice is urgent.