Lignin Mimicking Protein Methylation Augments the Efficacy of FOLFOX Chemotherapy by Anchoring Thymidylate Synthase.

FOLFOX has served as the standard chemotherapy regimen for advanced stages, specifically in the treatment of pancreatic, colorectal, and bladder cancers. However, the issues of excessive toxicity and prolonged treatment cycles persist. To address this limitation, we developed a novel methylated amino acid-modified lignin inspired by biological methylation, creating a pH-responsive charge-reversal drug delivery system for FOLFOX chemotherapy. This system stabilizes thymidylate synthase (TS) and combines with deoxyuridine monophosphate (dUMP) to demonstrate significantly improved therapeutic outcomes of FOLFOX against colorectal cancer (CRC). The FOLFOX-loaded nanodrug showed targeted antitumor activity against CRC and induced tumor cell death through multiple mechanisms, including apoptosis, necrosis, cell cycle regulation, DNA damage, and reactive oxygen species generation. Furthermore, the nano-formulation activated immune responses to enhance chemotherapeutic potency and effectively reducing renal toxicity associated with chemotherapy drugs. These findings suggest that protein methylation-mimicked lignin could be a valuable addition to current first-line chemotherapy options and holds promise for enhancing chemotherapy against solid tumors.