Bi‐Functional Topospecific Nanoparticles to Promote Immune‐Tumor Cell Engagement as A New Immunotherapeutic Strategy

Abstract Cancer immunotherapy has emerged as a promising alternative approach, enabling the body's immune system to fight cancer. Cytotoxic T cells play a pivotal role in recognizing and eliminating tumor cells, and their effectiveness relies on establishing a physical interaction and efficient communication with cancer cells. However, this communication is often disrupted by immune escape mechanisms, allowing cancer progression. A versatile nanoplatform is developed to restore cellular connection using Janus mesoporous silica‐Au nanoparticle (J‐pHLIP‐PD1), including specific binding sites on opposite faces for simultaneous binding to cancer cells and immune cells. The two differential surfaces on the nanoparticle allow orthogonal functionalization with the anti‐PD‐1 antibody that interacts with the PD‐1 receptor in cytotoxic T cells on the gold face and the pH Low Insertion Peptide (pHLIP), which undergoes specific insertion into the tumor cell membrane on the silica face. J‐pHLIP‐PD1 nanoparticles effectively bind the surface of tumor cells and capture T cells, facilitating the formation of immune synapse‐like structures that lead to reduced cancer cell viability in vitro, associated with immunogenic cell death signatures. The therapeutic potential of J‐pHLIP‐PD1 is also demonstrated in an in vivo metastatic melanoma model, where treatment with J‐pHLIP‐PD1 produces a significant decrease in metastatic burden and increases T cell presence. The Janus nanosystem represents an attractive platform that expands the toolbox of immune‐engaging strategies, offering a flexible alternative to conventional immunotherapies that link immune and tumor cells, restoring cell–cell communication for cancer elimination.