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However, the issues of excessive toxicity and prolonged treatment cycles persist. To address this limitation, we developed a novel methylated amino acid\u2010modified lignin inspired by biological methylation, creating a pH\u2010responsive charge\u2010reversal 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\u2010loaded 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\u2010formulation activated immune responses to enhance chemotherapeutic potency and effectively reducing renal toxicity associated with chemotherapy drugs. 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