Cell Membrane-Targeted J-Aggregation Strategy for Synergistic Immune Checkpoint Degradation and Immunogenic...

While immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, limitations persist due to factors like PD-L1 recycling, immunosuppressive tumor microenvironments, and off-target effects. Here, we present a novel cell membrane-targeted J-aggregation strategy that synergistically combines immune checkpoint degradation with photo-controlled immune activation within a single-component system. Our platform utilizes a unique PD-L1 ligand-dye conjugate that self-assembles into highly-ordered J-aggregate, maximizing the surface exposure of ligands and imparting remarkable NIR absorption and hypoxia-tolerant type-I photodynamic activities. Surface ligands facilitate multivalent binding to PD-L1 on tumor cell membranes, triggering its lysosomal degradation and leading to a sustained reduction in cellular PD-L1 abundance across diverse cell lines. NIR light irradiation then drives potent immunogenic pyroptosis even under extremely hypoxic conditions (down to 0.1% O₂), due to the organelle-targeted type-I photodynamic effect on cell membrane and lysosomes. This targeting arises from the initial PD-L1-mediated membrane binding and subsequent trafficking to lysosomes. Moreover, our platform enables drug self-delivery, coupled with the EPR effect and active targeting of tumor PD-L1, resulting in excellent tumor-selective accumulation (up to 9.8%ID/g). In vivo studies validate a synergistic antitumor immune response. This versatile strategy, applicable to various membrane proteins, represents a significant advance in immunotherapy, opening new avenues for more effective tumor immunotherapies.