Nanometabolomics Elucidated Paclitaxel/Mo_4/3B_2–<i>x</i> Bifunctional Nanomedicine-Based Lung Cancer Therapy through Regulated Amino Acid Metabolism

Lung cancer (LC) remains the leading cause of cancer death worldwide. Chemical combined photothermal therapy (PTT) offers an innovative therapeutic strategy for LC. However, the mechanistic understanding of PTT-based LC treatment lacks deep mechanistic insights into photothermal therapy. In this work, we developed a paclitaxel/Mo_4/3B_2-<i>x</i> bifunctional nanomedicine (Taxol/Mo_4/3B_2-<i>x</i>-BN) for the treatment of LC. Mo_4/3B_2-<i>x</i> nanosheets could reduce drug resistance or degradation of Taxol, while Taxol could enhance post-PTT residual cell elimination. Furthermore, nanometabolomics was leveraged to investigate metabolic reprogramming, specifically alterations in the metabolome and lipidome, at the molecular level following treatment. Results demonstrated that 1 mg/mL Taxol/Mo_4/3B_2-<i>x</i>-BN exhibited excellent biocompatibility and synergistic efficacy, inducing a rapid tumor volume regression (from 0.214 cm³ to complete resolution on day 4). Subsequent nanometabolomics revealed significant alteration in amino acids and lipid metabolism, which demonstrated that Taxol/Mo_4/3B_2-<i>x</i>-BN could regulate the homeostasis of amino acid and lipids metabolism. Key amino acid metabolic pathways induced by treatment were further delineated. These findings indicate the clinical anticancer potential of Taxol/Mo_4/3B_2-<i>x</i>-BN. In addition, nanometabolomics could provide multidimensional bioinformation for nanomedicine-based mechanism exploration.