Manganese-Mediated CD47 Epitope-Imprinted Nanotraps for Stage-Adaptive Macrophage Reprogramming and Photothermal...

Current macrophage-centric immunotherapies face limitations in systemic toxicity, targeting precision, and stage-specific adaptability. To address these challenges, we engineer manganese-mediated CD47 epitope-imprinted nanotraps (Mn-MIP nanotraps) via a facile one-pot synthesis. Molecular imprinting creates high-affinity cavities enabling 2.63-fold enhanced CD47 recognition over nonimprinted controls, effectively blocking the "do not eat me" signal. Tumor microenvironment-triggered Mn²⁺ release repolarizes immunosuppressive M2 macrophages into tumoricidal M1 phenotypes with 1.96-fold increased CD86⁺ populations. Near-infrared irradiation further induces immunogenic cell death, enhancing calreticulin exposure and HMGB1 release. These drug-free platforms confer stage-adaptive efficacy: early-stage tumors show 79.1% regression through macrophage-centric innate immunity alone, whereas advanced tumors require combined innate/adaptive immune activation to achieve 98.7% suppression. The nanotraps demonstrate exceptional biosafety (<10% hemolysis, preserved organ function) and readily scalable manufacturing. This work establishes molecularly imprinted nanotechnology as a versatile drug-free strategy for precision immunotherapy, effectively addressing the dynamic challenges of cancer progression.