X-ray-Triggered Nanoadjuvant Enabling Spatiotemporal Immunometabolic Modulation for Pyroptosis-Enhanced Radiotherapy

Radiotherapy efficacy is limited by an immunosuppressive tumor microenvironment (TME). Current immunometabolic strategies using nonselective inhibitors or exogenous stimulus-activated nanomedicines suffer from off-target toxicity, insufficient antitumor responses, and procedural complexity. Herein, we developed PLG@OMVs-VP, an X-ray-activatable nanoadjuvant, to remodel the immunosuppressive TME and amplify the radiotherapy efficacy. PLG@OMVs-VP comprises outer membrane vesicles (OMVs) modified with verteporfin (VP) and an indoleamine 2,3-dioxygenase inhibitor (NLG-919) via a PEGylated singlet oxygen (1O2)-cleavable linker. Upon X-ray radiation, VP absorbs X-rays and generates 1O2, which not only induces immunogenic tumor cell death via radiodynamic therapy but also triggers the selective release of NLG-919 for immunometabolic regulation. Moreover, the intrinsic lipopolysaccharide on OMVs activates pyroptosis, further enhancing the tumor immunogenicity. This strategy integrates pyroptosis-induced immunogenicity, radiodynamic therapy, and spatially controlled immunometabolic regulation, synergistically alleviating TME immunosuppression and eliciting antitumor immunity in both primary and distant tumors. This X-ray-activatable nanoplatform enables TME remodeling and an enhanced radiotherapy.