NK cell biomimetic MOF nanoplatform disrupts hypoxia adaption for complete tumor ablation.

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its immunosuppressive and hypoxic microenvironment. We developed NKAMP, a biomimetic nanoplatform that synergistically overcomes immune evasion and hypoxia resistance through three synergistic mechanisms: (1) intelligent dual-targeting (NK cell membrane CD226/NKG2D plus MUC1 aptamer) to ensure robust and redundant targeting, (2) drug release to inhibit HIF-1α function and disrupt hypoxia adaption, and (3) immune-compatible photodynamic therapy (PDT). This design allows NKAMP to overcome physical, immunological, and hypoxic barriers simultaneously, achieving 3.04-fold higher tumor accumulation and 71.88% HIF-1α suppression. The resulting hypoxia adaptation disruption created a self-reinforcing ROS amplification cycle (1.53-fold increase), inducing mitochondrial apoptosis and achieving complete tumor ablation in vivo (96.16% volume reduction) with 10.9 times efficacy improvement than PCN-224 alone. By reprogramming the tumor microenvironment through immune-compatible PDT, this platform establishes a new “immune-compatible PDT” paradigm that addresses TNBC’s intertwined challenges.