Non‐Enzymatic Destruction of the Extracellular Matrix for Activatable Orthotopic Tumor Treatment and Enhanced Drug Penetration

Abstract The controlled release and enhanced penetration of drugs to deep‐seated tumors is highly desirable but faces many challenges. Herein, supramolecular biomimetic nanoaggregates (HFCu NAs) are constructed with fluorinated histidine and copper ions via multivalent interactions (metal coordination and aromatic packing), affording tumor microenvironment responsive “turn‐on” 19 F magnetic resonance imaging 19 F MRI guided drug delivery and specific tumor therapy. By virtue of ligand engineering and pH‐triggered conformation changes, HFCu NAs exhibit enhanced reactive oxygen species ROSgeneration due to lower pH levels at tumor sites, leading to the stepwise collapse of the extracellular matrix (ECM), which is analogous to targeted protein degradation, without requiring endogenous enzymes. Consequently, the breakdown of the ECM provides positive feedback for the permeation of HFCu NAs, thereby, significantly inhibiting orthotopic tumor growth with explicit immunogenic cell death. As such, the proposed platform exhibits significant potential as activatable drug delivery vehicles for enhanced drug permeation and therapy.