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

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.