【Title】Allomelanin-based biomimetic nanotherapeutics for orthotopic glioblastoma targeted photothermal immunotherapy

【Abstract】Immune checkpoint blockade (ICB) therapy has shown great potential in the treatment of malignant tumors, but its therapeutic effect on glioblastoma (GBM) is unsatisfactory because of the low immunogenicity and T cell infiltration, as well as the presence of blood-brain barrier (BBB) that blocks most of ICB agents to the GBM tissues. Herein, we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted photothermal therapy (PTT) and ICB synergistic therapy by loading immune checkpoint inhibitor CLP002 into the allomelanin nanoparticles (AMNPs) and followed by coating cancer cell membranes (CCM). The resulting AMNP@CLP@CCM can successfully cross the BBB and deliver CLP002 to GBM tissues due to the homing effect of CCM. As a natural photothermal conversion agent, AMNPs are used for tumor PTT. The increased local temperature by PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells. Importantly, PTT can effectively stimulate immunogenic cell death to induce tumor-associated antigen exposure and promote T lymphocyte infiltration, which can further amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Therefore, AMNP@CLP@CCM has great potential for the treatment of orthotopic GBM by PTT and ICB synergistic therapy.

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