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Atherosclerosis (AS) is a chronic inflammatory disease that leads to the formation of atherosclerotic plaques in arterial walls, which can eventually result in cardiovascular diseases. It has been confirmed that the imbalance in the polarization of M1-type pro-inflammatory and M2-type anti-inflammatory macrophages in AS plaques is closely related to plaque instability and the development of cardiovascular diseases like AS-related heart and cerebrovascular diseases. Triptolide (TP) is a promising drug for the treatment of AS due to its anti-inflammatory and anti-proliferative effects. However, its poor solubility and lack of specificity limit its clinical application. We developed a targeted delivery system for TP to M1-type macrophages using mesoporous polydopamine (MPDA) nanospheres modified with the LyP-1 peptide. We then observed the performance of this targeted delivery system and explored its regulatory effects on macrophage polarization in AS. The results showed that the LYP-1-modified MPDA-TP delivery system had an average encapsulation rate of 66.5%, a drug loading capacity of 4.5%, and an average diameter of 250 nm. It exhibited excellent targeting ability and drug release rate towards target cells. LYP-MPDA-TP was capable of inhibiting the proportion of M1 macrophages induced by oxidized low-density lipoprotein stimulation in mouse macrophages, promoting apoptosis in M1-type macrophages significantly, and demonstrating a significant inhibitory effect on AS in experimental animals. The LYP-1 peptide-modified MPDA delivery system provides a new approach for TP treatment of AS and an important theoretical basis and methodological reference for the design of targeted delivery systems for anti-AS nanoparticles.

Objective: Gene mutations in tumor cells can lead to several unique metabolic phenotypes, which are crucial for the proliferation of cancer cells. EGFR mutation (EGFR-mt) is the main oncogenic driving mutation in lung adenocarcinoma (LUAD). HIF-1 α and PKM2 are two key metabolic regulatory proteins that can form a feedback loop and promote cancer growth by promoting glycolysis. Here, the linkage between EGFR mutational status and HIF-1α/PKM2 feedback loop in LUAD were evaluated., Methods: Retrospective study were performed on LUAD patients ( n  = 89) undergoing first-time therapeutic surgical resection. EGFR mutation was analyzed by real-time PCR. Immunohistochemistry was used to measure the expressions of HIF-1α and PKM2., Results: We found that the protein expressions of HIF-1α and PKM2 were significantly higher in LUAD than normal lung tissues. In adenocarcinomas, the two protein expressions were both correlated with worse pTNM stage. Moreover, the correlation between the proteins of HIF-1α/PKM2 feedback loop and the EGFR mutational status were also analyzed. We found that EGFR-mt tumors showed higher HIF-1α and PKM2 proteins compared to tumors with EGFR wild-type. Meanwhile, HIF-1α expression was significantly correlated with higher pTNM stage, and PKM2 showed a similar trend, only in EGFR-mutated tumors. The expression of HIF-1α was positively correlated with PKM2 in LUAD, furthermore, this correlation was mainly in patients with EGFR-mt., Conclusion: Different expression and clinical features of HIF-1α/PKM2 feedback loop was existed between LUAD and normal lung tissues, especially in EGFR mutational tumors, supporting the relationship between EGFR mutation and the key related proteins of aerobic glycolysis (HIF-1α and PKM2) in lung adenocarcinomas.