Targeting PD‑1 in CD8⁺ T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine–Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma

We fabricated bilirubin–bovine serum albumin (BR–BSA) nanocomplexes as candidates for the delivery of 5-fluoro-2-deoxyuridine (5FUdr) against experimental murine lymphoma. BR was attached to 5FUdr via acid-labile ester bonds mimicking small-molecule drug conjugates. The construct was self-assembled with BSA through strong noncovalent interactions with high drug occupancy in the core and labeled with folic acid (FA) to target cancer cells. The BR–5FUdr–BSA–FA nanoconstruct exhibits excellent biocompatibility, prevents nephrotoxicity, and is tolerated by red blood cells and mononuclear cells. The construct also showed increased accumulation in lymph nodes and tumor cells. BR–5FUdr–BSA–FA caused prolonged growth inhibition and apoptosis, enhanced mitochondrial reactive oxygen species generation, and minimized the viability of parental and doxorubicin-resistant Dalton’s lymphoma cells. Treatment of tumor-bearing mice with BR–5FUdr–BSA–FA significantly increased the life span of the animals, improved their histopathological parameters, and downregulated PD-1 expression, suggesting the potential of the construct for 5FUdr delivery to treat lymphoma.