Engineered Biomimetic Nanovesicles Synergistically Remodel Folate-Nucleotide and γ-Aminobutyric Acid Metabolism to Overcome Sunitinib-Resistant Renal Cell Carcinoma

作者：Minchao Lv, Bin Liu, Yi Duan, Yi Duan, Jiangtao Lin, Dai Li, Yuanyuan Li, Jian Yu, Jinghan Liao, Jiali Zhang, Yourong Duan, Yourong Duan · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.4c08055 · 被引用次数：9 · 研究领域：Nanoplatforms for cancer theranostics、Adenosine and Purinergic Signaling、Nanocluster Synthesis and Applications

Reprogramming of cellular metabolism in tumors promoted the epithelial-mesenchymal transition (EMT) process and established immune-suppressive tumor microenvironments (iTME), leading to drug resistance and tumor progression. Therefore, remodeling the cellular metabolism of tumor cells was a promising strategy to overcome drug-resistant tumors. Herein, CD276 and MTHFD2 were identified as a specific marker and a therapeutic target, respectively, for targeting sunitinib-resistant clear cell renal cell carcinoma (ccRCC) and its cancer stem cell (CSC) population. The blockade of MTHFD2 was confirmed to overcome drug resistance via remodeling of folate-nucleotide metabolism. Moreover, the manganese dioxide nanoparticle was proven here by a high-throughput metabolome to be capable of remodeling γ-aminobutyric acid (GABA) metabolism in tumor cells to reconstruct the iTME. Based on these findings, engineered CD276-CD133 dual-targeting biomimetic nanovesicle EMφ-siMTHFD2-MnO 2 @Suni was designed to overcome drug resistance and terminate tumor progression of ccRCC. Using ccRCC-bearing immune-humanized NPG model mice, EMφ-siMTHFD2-MnO 2 @Suni was observed to remodel folate-nucleotide and GABA metabolism to deactivate the EMT process and reconstruct the iTME thereby overcoming the drug resistance. In the incomplete-tumor-resection recurrence model and metastasis model, EMφ-siMTHFD2-MnO 2 @Suni reduced recurrence and metastasis in vivo. This work thus provided an innovative approach that h...