Cascade Structural Transition of Salicylic Acid Nanoassemblies for Enhanced Label‐Free Tumor Magnetic Resonance Imaging and Self‐Reporting Precise Therapy

Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking specific molecular targets, hindering effective therapy and real‐time efficacy monitoring. Here, we present an innovative, streamlined self‐reporting nanoprobe, NapYpSA, addressing these challenges without additional probe labeling. NapYpSA nanospheres first undergo alkaline phosphatase (ALP)‐induced internalization and dephosphorylation, improving cellular uptake and promoting the transition to dense NapYSA nanofibers in ALP‐overexpressing TNBC cells. Subsequently, esterase hydrolysis slowly releases salicylic acid (SA), which inhibits COX‐2 and activates a chemical exchange saturation transfer (CEST) MRI signal, further transforming the NapYSA nanofibers into sparse NapY nanofibers for post‐apoptotic clearance. By combining in situ nanofiber transformation‐induced disruption of microtubule polymerization with enhanced COX‐2 inhibition mediated by SA accumulation, this cascade enzymatic cleavage‐triggered nanostructure transition not only improves tumor treatment efficacy but also reduces toxic side effects. Moreover, the increased local SA concentration also amplifies the CEST signal, enabling real‐time tracking of drug activation with a clinical 3.0 T MRI scanner. In vivo studies demonstrated that ALP activity, CEST signal intensity, and antitumor efficacy were closely linked. Therefore, this self‐reporting strategy not only enhances TNBC therapy but also enables CEST MRI‐guided identification of highly responsive tumors at treatment initiation, thereby facilitating precise therapeutic intervention.