Inducing Cuproptosis with Copper Ion‐Loaded Aloe Emodin Self‐Assembled Nanoparticles for Enhanced Tumor Photodynamic Immunotherapy

Immunotherapy has fundamentally transformed the clinical treatment landscape for non-small cell lung cancer (NSCLC). While its effectiveness is ultimately limited by patient heterogeneity and immunosuppressive tumor microenvironment. Photodynamic therapy (PDT), as an emerging antitumor immunotherapy, has shown its unique therapeutic advantages. However, previous studies often overlooked the potential toxicity of photosensitizers (PS), making the discovery of safe and effective PS a pressing clinical need. In this study, Aloe Emodin (AE), a medicinal plant natural compound, was loaded with copper ions (Cu), and self-assembled into nanoparticles (NPs) under the modification of PEG2k-DSPE-FA. NPs can target, accumulate, and reside within tumor sites, responsively releasing copper ions and AE, thus dual-functioning by inducing tumor cell death via cuproptosis and enhancing PDT effects. The LLC tumor-bearing mouse model demonstrated that NPs induce the maturation of dendritic cells (DCs) in vivo, promote lymphocyte infiltration, transform "cold tumors" into "hot tumors" and significantly enhance the efficacy of immune checkpoint blockade (ICB). This study provides experimental evidence of AE as a clinically promising PDT agent and offers a novel perspective for the synergistic treatment of clinical NSCLC.