Abstract

Leucine-rich α-2-glycoprotein 1 (LRG1) is markedly upregulated in colorectal cancer (CRC) and correlates with a poor prognosis, yet its role in drug response remains unclear. Here, we identify an association between LRG1 and thymidylate synthase (TYMS) that influences 5-fluorouracil (5-FU) sensitivity in CRC. LRG1 silencing is associated with reduced TYMS expression and enhanced 5-FU cytotoxicity, an effect partially mediated through the PI3K-AKT-mTOR signaling pathway. Guided by these observations, we constructed a lysosome-targeting liposomal nanochimera (Lipo-EM@5-FU) that integrates targeted degradation of LRG1 with 5-FU chemotherapy to achieve coordinated modulation of signaling and metabolic processes. Upon uptake, lysosomal degradation of LRG1 is associated with attenuation of PI3K-AKT-mTOR signaling and reduced TYMS expression, while 5-FU further blocks its enzymatic activity, contributing to cell cycle arrest and apoptosis. In tumor-bearing mice, Lipo-EM@5-FU achieves prolonged circulation, enhanced tumor accumulation, and potent antitumor efficacy with minimal systemic toxicity. This work reveals a functional link between LRG1 and 5-FU responsiveness, establishing a degradation-driven chemosensitization paradigm for colorectal cancer therapy.