Necroptosis‐Mediated Synergistic Photodynamic and Glutamine‐Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma

Abstract Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R‐CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species‐responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg‐Gly‐Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R‐CM@MSN@BC executed both photodynamic and glutamine‐metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time‐of‐flight mass cytometry analysis revealed that R‐CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1‐type macrophages, reducing infiltration of M2‐type and CX3CR1 + macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti‐programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.