Cascaded multiresponsive supramolecular dimer-engineered nano-modulator enabling spatiotemporally adaptable tumor immune microenvironment remodeling in photodynamic immunotherapy

Cancer immunotherapy emerges as a promising therapeutic modality, while its clinical application remains constrained by low tumor immunogenicity and immunosuppressive microenvironments. Herein, we report a unique superdimeric nanoassembly pattern by elaborately integrating cyclodextrin inclusion with dimeric prodrug, enabling spatio-temporally self-adaptive drug delivery and multimodal photo-immunotherapy. Specifically, it is precisely engineered through host-guest inclusion between a GSH-sensitive cyclodextrin-photosensitizer conjugate and an oxidation-responsive homodimer prodrug of NLG919. Notably, on-demand photosensitizer activation and aggregation-caused quenching relief significantly facilitates photodynamic induction of ICD. Meanwhile, photodynamic ROS together with the endogenous ROS collaboratively facilitate on-demand NLG919 activation and release, efficiently reversing the immunosuppressive microenvironments. As such, the superdimeric nanoassembly allows spatio-temporally cascade-potentiated photo-immunotherapy, starting from photosensitizer activation to ICD induction, NLG919 release and IDO inhibition. Finally, it exerts intense antitumor efficacy, abscopal effect and synergy with PD-L1 antibody in two mouse models. This study presents new insights into the design of nanomedicines for multimodal photo-immunotherapy.