On‐Demand ER Stress Modulation in Tumor Cells and TAMs via an Adaptively Transformable Nanoplatform Enhances Photodynamic Immunotherapy

Abstract Photodynamic therapy (PDT) induces tumor immunogenic cell death (ICD) primarily through activating endoplasmic reticulum (ER) stress in tumor cells. However, ER stress is shown to promote the activation and proliferation of the immunosuppressive tumor‐associated macrophages (TAMs), which are pivotal drivers of immune evasion. Coordinating the conflicting demands of ER stress signaling pathways in tumor cells and TAMs is crucial for potentiating PDT‐based immune therapy. Here, an adaptively transformable nanoplatform (G@MDHP) is developed to facilitate the respective delivery of a photosensitizer and an ER stress inhibitor into tumor cells and TAMs efficiently. G@MDHP, which mimics the surface change of erythrocytes throughout their life span to cater for the rejection or phagocytosis by macrophages, exhibits prolonged circulation due to its surface CD47 peptide, while undergoing shell exfoliation in the presence of matrix metalloproteinase‐9 (MMP‐9) to expose mannose‐functionalized core nanoparticles (G@MD). The disassociated G@MD, carrying the inhibitor, specifically inhibits ER stress in immunosuppressive TAMs for efficient phenotype switch. Meanwhile, the disassociated shell containing a photosensitizer is rapidly internalized by tumor cells to exert PDT‐induced ER stress amplification and provoke a robust ICD. This dual action of core and shell components thus establish a cooperative anti‐tumor immune network, bringing about significant therapeutic benefits.