Apart from the blood-brain barrier (BBB), the efficacy of immunotherapy for glioblastoma (GBM) is also limited by intrinsic immune resistance represented by extremely low immunogenicity and adaptive immune resistance represented by an immunosuppressive microenvironment. This implies the need for the combined delivery of multiple immunotherapeutic agents or simultaneous regulation of different cells. However, the differences in physicochemical properties among various immunotherapeutic agents pose significant challenges for the selection of carriers and the design of co-delivery systems. Bacterial outer membrane vesicles (OMVs) are nanoscale bilayer lipid vesicles spontaneously produced by Gram-negative bacteria. They possess unique advantages in treating GBM due to their multifunctional characteristics as carriers (similar to exosomes), immune adjuvants (inheriting many immunogenic components from the outer membrane and periplasm of the parent bacteria), and the ability to cross the BBB (based on the interaction between outer membrane proteins and gp96 or by hitchhiking on neutrophils). However, traditional OMVs can cause toxic side effects and damage to the BBB tight junctions after systemic administration.

In view of this, the research team led by Associate Professor Tao Sun and Professor Chen Jiang introduced engineered OMVs to reduce toxicity and further constructed a modularly assembled nanoplatform through simple peptide modification. This nanoplatform demonstrates satisfactory biocompatibility and is capable of continuously crossing the BBB and targeting GBM with the assistance of Angiopep-2. Subsequently, the immunogenic substances on the OMVs along with carried CD47-siRNA and doxorubicin can promote and enhance the reprogramming and phagocytic abilities of macrophages and microglia, respectively, and increase the immunogenicity of GBM, ultimately overcoming GBM immune resistance to enhance the efficacy of immunotherapy. The related research results were published online in the international renowned journal Advanced Materials under the title “Engineered Bacterial Outer Membrane Vesicles-Based Doxorubicin and CD47-siRNA Co-Delivery Nanoplatform Overcomes Immune Resistance to Potentiate the Immunotherapy of Glioblastoma”.

Haoyu You, the PhD candidate from the School of Pharmacy, Fudan University, is the first author. Associate Professor Tao Sun and Professor Chen Jiang are the corresponding authors of this paper. The work was supported by grants from the National Natural Science Foundation of China, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, and ZJLab.

For more information: https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/adma.202418053