TMP-195

Tumor immunotherapy represents a highly promising modality for the treatment of triple‐negative breast cancer (TNBC). Nevertheless, its therapeutic efficacy has been profoundly impacted by challenges such as low drug uptake, hypoxia, and immunosuppression. To address these problems, the study develops a strategy combining sonodynamic therapy (SDT) and immunotherapy using biomimetic nanoparticles coated with hybrid membranes. The nanoparticles are loaded with semiconducting polymers (PFODBT), Atovaquone (ATO), and TMP195 to enhance biocompatibility, targeting ability, and drug uptake and retention at the tumor site. In in vitro experiments, the biomimetic nanoparticles alleviate hypoxia, induce immunogenic cell death (ICD), and prompt reprogramming of tumor‐associated macrophages (TAMs) from M2 type to M1 type. In in vivo experiments, the synergistic effects of enhanced SDT‐mediated ICD and TAMs repolarization significantly inhibit the proliferation of primary and distant tumor in the 4T1 subcutaneous tumor model, and effectively attenuated metastasis of lung and liver. Moreover, the in vivo immune responses are further activated by improving the maturation of dendritic cells, filtration of CD8+ T cells, and depletion of regulatory T cells. This study offers a novel strategy for TNBC therapy by converting the tumor microenvironment from the “cold” into “hot” tumor through multiple synergistic therapies.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the β-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.