Mesoporous Microneedles\nEnabled Localized Controllable\nDelivery of Stimulator of Interferon Gene Agonist Nanoexosomes for\nFLASH Radioimmunotherapy against Breast Cancer

The immunosuppressive nature of the tumor microenvironment\n(TME)\ncontributes to radioresistance, thereby impairing the effectiveness\nof radiotherapy as a therapeutic intervention. Activation through\nthe stimulator of interferon genes (STING) pathway shows potential\nin modulating immunogenicity. However, the therapeutic efficacy of\nSTING agonists might be restricted by off-target effects and potential\ncytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous\nmicroneedles were employed for precise delivery of the STING agonist\nMSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration\nenabled by microneedles, EXOs can be continually released and accumulate\nwithin deep residual tumors. Once internalized, these EXOs release\nthe encapsulated MSA-2, facilitating the activation of the STING pathway\nupon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy\nelevates the type I interferon level, promotes dendric cell maturation,\nand modulates the immunosuppressive TME, showing efficient antitumor\nefficacy in both primary/metastatic tumors. Furthermore, the induction\nof a potent immune response effectively prevented tumor recurrence.\nThe combination of EXO-loaded microneedles with FLASH radiotherapy\nresulted in minimal systemic side effects, attributed to precise drug\ndelivery and radioprotection conferred by FLASH. Altogether, the strategic\ndesign of EXO-loaded microneedles holds promise for enhancing MSA-2\ndelivery, thereby mitigating the radioresistant tumor microenvironment\nthrough STING cascade activation-mediated immunotherapy, consequently\noptimizing the outcomes of FLASH radiotherapy.