Engineered Bacterial Outer Membrane Vesicles‐Based Doxorubicin and CD47‐siRNA Co‐Delivery Nanoplatform Overcomes Immune Resistance to Potentiate the Immunotherapy of Glioblastoma

Abstract Apart from the blood‐brain barrier (BBB), the efficacy of immunotherapy for glioblastoma (GBM) is limited by the presence of intrinsic and adaptive immune resistance, implying that co‐delivery of various immunotherapeutic agents or simultaneous regulation of different cells is urgently needed. Bacterial outer membrane vesicles (OMVs) offer a unique advantage in the treatment of GBM, owing to their multifunctional properties as carriers and immune adjuvants and their ability to cross the BBB. However, traditional OMVs can lead to toxic side effects and disruption of tight junctions in the BBB. Therefore, to enhance the in vivo safety and targeting capability of OMVs, we introduced engineered OMVs to reduce toxicity and further constructed a modularly assembled nanoplatform by performing simple peptide modifications. This nanoplatform demonstrates satisfactory biosafety and is able to continuously cross the BBB and target GBM with the assistance of Angiopep‐2. Subsequently, immunogenic substances on OMVs, along with carried small‐interfering RNA (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. This OMVs‐based nanoplatform provides a new paradigm and insights into the development of immunotherapy for GBM.