Co-delivery of panobinostat and siSTAT3 using engineered M1 exosomes to establish a one-two punch therapeutic strategy for glioblastoma recurrence.

Effectively treating recurrent glioblastoma (GB) remains a significant challenge in the clinic. Considering the multifactorial nature of GB progression, a comprehensive therapeutic strategy that directly targets both the tumor cells and its microenvironment is crucial. In this study, we developed an approach using exosomes derived from genetically modified M1 macrophages that encapsulate panobinostat and siSTAT3 to treat recurrent GB. We demonstrate that this innovative system has an innate ability to actively home to tumor cells, leveraging the inflammation-targeting capabilities of M1 macrophage-derived exosomes. These exosomes are pivotal in shifting the balance from M2 macrophages to the more favorable M1 phenotype within the tumor microenvironment. By loading the exosomes with panobinostat, a compound that faces challenges crossing the blood-brain barrier, it can efficiently access and act upon the tumor. Moreover, with the co-delivery of siSTAT3, the exosomes display various functionalities, such as inhibiting GB proliferation and invasion, preventing astrocyte reactivity, and reducing M2 macrophage infiltration. This "one-two punch" approach offers a powerful combined anticancer effect through simultaneously targeting tumor cells and reshaping the tumor microenvironment, which holds considerable promise in curbing GB recurrence and provides hope for more effective future treatments.