Cell Membrane-Targeted J-Aggregation Strategy for Synergistic Immune Checkpoint Degradation and Immunogenic Pyroptosis to Augment Tumor Immunotherapy.

Abstract

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.