To address this, we developed a TME-responsive polymeric micelle co-delivering alpelisib (a pan-PI3K inhibitor) and cobomarsen (a miR-155-5p inhibitor) for targeted therapy. This dual-targeting strategy effectively suppressed PIK3CA-mutated tumor growth and epithelial-mesenchymal transition. These findings reveal the role of MDSC-driven metastatic potential via the exosomal miR-155-5p/SIRT1 axis in HR + breast cancer and present a novel nanotherapeutic approach for precision intervention.

The novelty of the study lies in the development of a precise and targeted therapeutic approach tailored to HER2-positive breast cancer, addressing critical gaps in current treatment modalities. Our findings underscore this innovative formulation's clinical relevance and translational potential, paving the way for personalised and effective therapies in HER2-positive breast cancer management.

It was found that miR-155 antagomir delivery using exosomes can inhibit migration, invasion, and angiogenesis viaPTEN and DUSP14 in TNBC.

A xenograft tumor model was used to show that GQ and miR-451 amplified the antitumor effect of ADR in nude mice, while western blot and immunohistochemical assays revealed the decreased expression of P-gp in tumor tissues. These results suggest that GQ and miR-451 have synergistic effect on reversing drug resistance through reducing the expression of MDR1 and P-gp in breast cancer MCF-7/ADR cells.

After synergistic treatment, the NF-κB pathway was significantly blocked, thereby generating strong anti-metastatic ability both in vitro and in vivo. The poly-antioxidant could be a new type of nanoplatform for highly efficient and safe miRNA delivery, which also provides a promising strategy for the synergistic treatment of metastatic breast cancer.

Mammary glands excised from tumors of mice deficient in miR155 exhibited even greater inhibition of M2 macrophages, important in reducing inflammation and contributing to tumor growth and immunosuppressive function, as indicated by reduced IL-4, IL-10, IL-13, mannose receptor 1 (Mrc1), and TNF-beta. Given that macrophages are known to promote tumorigenesis, we suggest that the anti-tumor effects of miR155 inhibition are due to its upregulation of SOCS1 and resulting decrease in pro-tumor M2 macrophages.

We also found that CLL cells directly regulate miR155 levels in TN, thereby affecting Th17 differentiation by documenting that: co-culturing TN with resting (Brest) or activated (Bact) CLL cells alters the magnitude and direction of T-cell miR155 levels; CLL Bact promote IL17A+ and IL17F+ T cell generation by a miR155-dependent mechanism, confirmed by miR155 inhibition; co-cultures of TN with CLL Bact lead to a linear correlation between the degree and direction of T-cell miR155 expression changes and IL17F production, but not IL17A; Bact-mediated changes in TN miR155 expression correlate with outcome, irrespective of IGHV mutation status, a strong prognostic indicator. Together, the results identify a previously unrecognized CLL Bact-dependent mechanism, upregulation of TN miR155 expression and subsequent enhancement of IL17F+ Th17 generation, that favors better clinical courses.

The expression of miR-155 is up-regulated in bone marrow of children with B-ALL, which may be related to the activation of Wnt/β-Catenin signaling pathway promotes the proliferation of B-ALL cells and inhibits apoptosis, which leads to chemotherapy resistance.

Therefore, our findings indicate that exosomal delivery of miR-155 exerted the same effect as transfection did on the stemness maintenance and drug resistance of multiple myeloma cells.

Moreover, the exosomal miR-155 inhibitor suppressed the stem-cell-like property as well as drug efflux transporter protein expression in cisplatin-resistant tumors. Taken together, our findings, for the first time, established that the miR-155 inhibitor-loaded exosomes reverse chemoresistance in oral cancer, thereby providing an alternative therapeutic strategy for the management of refractory oral cancer patients.

Our findings showed that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known miR in MF and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumor burden.